CN114585365A - Use of parasympathomimetic agents alone or in combination with one or more alpha agonists to produce multifocal patients in pseudolens patients - Google Patents

Abstract

One or more parasympathomimetic agents are used alone or together, or in combination with one or more alpha agonists, to produce optically beneficial miosis, temporarily producing multifocal vision in pseudolens patients to treat presbyopia. A pharmaceutical formulation comprising a therapeutically effective amount of one or more parasympathomimetic agents or cholinesterase inhibitors, or pharmaceutically acceptable salts thereof, alone or in combination, in combination with one or more alpha agonists or antagonists, or pharmaceutically acceptable salts thereof. Also disclosed are methods of reducing presbyopia symptoms in one or both eyes of a patient by administering to one or more eyes a pharmaceutically effective amount of an ophthalmic formulation to produce multifocal in a pseudolens patient.

Description

Use of parasympathomimetic agents alone or in combination with one or more alpha agonists to produce multifocal patients in pseudophakic patients

Background

Technical Field

The present invention is in the field of treating optical disorders. More particularly, the present invention relates to the use of one or more parasympathomimetic agents or cholinesterase inhibitors, alone or in combination with one or more alpha agonists or antagonists, to produce optically beneficial miosis to induce multifocal in pseudocrystalline patients, e.g., to temporarily treat presbyopia.

Description of the related Art

Presbyopia is typically age-related eye degradation. Young, properly functioning eyes can be viewed at close distances, and this ability degrades with age. Presbyopia typically develops with age and is associated with a natural gradual loss of accommodation and naturally occurring stiffening of the lens with age. Presbyopic eyes lose the ability to quickly and easily focus on objects at close distances. Aging develops throughout the life of the individual and often becomes apparent after the age of 45. By age 65, lenses generally lose almost all of their elastic properties and have only a limited ability to change shape.

The use of over-the-counter presbyopic glasses is a very common way to address vision problems associated with presbyopia. Presbyopic glasses allow the eye to focus on close objects and maintain a clear image. This approach is similar to the treatment of hyperopia or hyperopia (farsight).

Many presbyopic subjects also employ bifocal glasses in which one portion of the lens corrects for distance vision and another portion of the lens corrects for near vision. When looking down through bifocal glasses, the individual views through the lens portion for near vision correction. When viewing distant objects, the individual looks higher through the portion of the bifocal glasses that corrects for distance vision. Contact lenses and intraocular lenses (IOLs) have also been used to treat presbyopia, for example, by relying on monocular vision (one eye for distance vision correction and the other eye for near vision correction) or bilateral correction with bifocal or multifocal lenses. Laser ablation has also been used to treat presbyopia. All of these procedures attempt to correct the problem over time using extreme measures (surgery, laser ablation, etc.) or require corrective lenses to be worn.

Many studies have attempted to determine the exact cause of presbyopia and various attempts have been made to reduce the effects of presbyopia using spectacles and contact lenses. These are of limited effectiveness. The use of pinhole glasses is also unsatisfactory because the pinhole does not move with the eye and the field of vision of the eye is limited. Pinhole eyewear also typically results in darkness when insufficient light reaches the retina.

Surgical methods to alleviate presbyopia include monocular vision, laser ablation, intraocular lens, and refractive lens replacement. Refractive corneal inlay generally increases corneal power in the non-dominant eye. These inlays require surgery. An intraocular lens (IOL) is an artificial lens. It replaces the natural lens of the eye that is removed during cataract surgery. The most common type of lens used for cataract surgery is known as a monofocal intraocular lens. It has a focus distance. It is set to focus near, intermediate or far vision. Most people set them for clear distance vision. Since these lenses are not able to correct presbyopia, patients often wear glasses for reading or working at close distances after surgery. Particular IOLs are known as multifocal and accommodating IOLs, having different focusing powers within the same lens. These IOLs reduce postoperative reliance on presbyopic glasses by providing increased near and far vision.

Another surgical approach to the treatment of presbyopia is AcuFocus^TMAn implant, which is a corneal implant, having a small central artificial pupil. The AcuFocu implant is similar to a washer with a hole in the middle, and is inserted under the corneal flap during surgery. The program restores reading vision by increasing the depth of focus. Surgery only for non-dominant eye movements appears to avoid the darkening problem that occurs when the pupils of both eyes become smaller.

Other refractive errors include myopia (nearsightedness), hyperopia (a condition in which light rays reach the retina before they converge in focus, resulting in global blurring) and astigmatism (defects in the curvature of the eye). Artificial refractive errors or visual distortions also often occur after laser surgery or when the natural lens is replaced by an artificial intraocular lens (e.g., during cataract surgery).

Cataracts are clouding of the lens in the eye that affects vision. Before cataract development, the lens was a transparent structure that helped focus light or images on the retina. Most cataracts are associated with aging. Most people develop cataracts after the age of 50 and have developed presbyopia. Cataracts are common in the elderly. Cataracts may occur in one or both eyes.

Canadian patent CA 2747095 by ant Sharma entitled "Optical Correction" discusses a drug for topical administration to the eye to improve visual acuity for hours and to provide benefits to users with presbyopia, myopia, hyperopia, astigmatism and/or impaired night vision. The medicament comprises two pharmacologically active agents-a parasympathetic agonist and a sympathetic antagonist or a sympathetic agonist. The parasympathetic agonist is pilocarpine, the sympathetic antagonist is selected from dapiprazole or moxidel, and the sympathetic agonist is selected from brimonidine or p-aminocyclopedine (iopidine). Eye drop formulations were prepared and tested on three individuals.

Each of the three subjects tested received the first and second eye drop formulations. The first drop of the ophthalmic formulation was 0.5% by weight of dapiprazole and 0.5% by weight of pilocarpine. The second eye drop formulation was 0.1% by weight brimonidine and 0.25% by weight pilocarpine.

Visual testing was performed before and after the administration of the eye drop formulation. In each case, the action was maintained for at least two hours, some for at least four hours.

The first individual was an emmetropic 63 year old, and did not require glasses for functional distance vision. Within 20 minutes after application, the patient's independent distance vision in each eye increased by one row on the snellen chart from 6/6 to 6/5. There was no change in refraction. At a reading distance of one-third of a meter, the patient's independent reading vision improves from N12 to N4.5. As described by the patient, the patient's night vision quality improved.

The second individual was a 50 year old myope (requiring glasses for functional distance vision) with-4 diopters. Within half an hour of administration, the patient's independent distance vision improved from being able to read several fingers (but not the snellen chart) to 6/36 on the chart. When wearing distance vision correction glasses, the reading vision of the patient at a distance of one third of a meter increases from N12 to N4.5. There was no change in refraction. Night vision quality improves as patients notice a reduction in halo and glare, and night vision also quantitatively improves from 6/6 to 6/5 in dim conditions.

The third individual was a 49 year old individual with +4 diopters of hyperopia (hyperopia and requiring glasses to obtain useful reading vision). Within half an hour of administration, the patient's independent distance vision improved from 6/60 to 6/24 on the snellen chart. The patient's independent reading vision at one third of a meter improved from N18 to N4.5. There was no change in refraction. Night vision quality improves, patients notice a reduction in halo and glare, and night vision also quantitatively improves from 6/6 to 6/5 in dim conditions.

The only side effect discussed in CA 2747095 was red eye, which was not experienced by any of the subjects.

The inventors of CA 2747095 hypothesize that the combination of parasympathetic and sympathetic agonists and antagonists has little or no effect on the ciliary muscles of the eye used to alter the shape of the lens and thus alter the refraction of the lens. However, ciliary muscles, as discussed below, are responsible for migraine.

The data for CA 2747095 was problematic because it was only tested on three individuals, some of whom were wearing corrective lenses and some were not. In addition, the effect of drops is not measured at time increments after they are received. Furthermore, no control test was performed on the individuals as a comparison to exclude placebo effects.

Accordingly, there remains a need for new methods of improving or reducing refractive errors including, but not limited to, presbyopia, hyperopia, myopia, pseudolenses, and disturbances caused by laser surgery in patients who do not wish to undergo surgery (IOL, laser ablation, etc.) or use corrective eyeglasses. There remains a need for temporary treatment of these disorders without the use of corrective lenses for those who use corrective lenses.

Disclosure of Invention

The pharmaceutical formulation comprises one or more parasympathomimetic agents, either alone or in combination with one or more sympathomimetic agents. The anti-sympathetic drug inhibits sympathetic nerve activity and includes an alpha-1 agonist and an alpha-2 agonist. In one embodiment, an ophthalmic topical formulation is provided comprising a therapeutically effective amount of one or more parasympathomimetic agents, or pharmaceutically acceptable salts thereof, alone or in combination with one or more alpha agonists or antagonists, or pharmaceutically acceptable salts thereof, that produces optically beneficial miosis, thereby inducing multifocal in pseudolens patients, e.g., to temporarily treat presbyopia.

A method for ameliorating or reducing optical error in a patient having at least one eye comprises administering to the at least one eye a therapeutically effective amount of an ophthalmic formulation comprising one or more parasympathomimetic agents or pharmaceutically acceptable salts thereof, alone or in combination with one or more alpha agonists or antagonists or pharmaceutically acceptable salts thereof.

A method for improving or reducing refractive error and producing multifocal vision in at least one eye of a pseudocrystalline patient comprises administering to the at least one eye a therapeutically effective amount of an ophthalmic formulation comprising one or more parasympathomimetic agents or pharmaceutically acceptable salts thereof, alone or in combination with one or more alpha agonists or antagonists or pharmaceutically acceptable salts thereof.

The invention also provides a method of inducing miosis in an eye in a subject comprising administering to the subject an amount of a formulation comprising one or more parasympathomimetic agents or pharmaceutically acceptable salts thereof and one or more alpha agonists or antagonists or pharmaceutically acceptable salts thereof effective to induce miosis in the eye, and one or more alpha agonists or antagonists.

The invention also provides a method of inducing ocular miosis in a subject to induce multifocal vision, the method comprising administering to the subject an amount of a formulation comprising one or more parasympathomimetic agents or pharmaceutically acceptable salts thereof, alone or in combination with one or more alpha agonists or antagonists or pharmaceutically acceptable salts thereof, and one or more alpha agonists or antagonists effective to induce ocular miosis.

A method for improving or reducing at least one refractive error selected from myopia, hyperopia, pseudocrystallography, and astigmatism in a patient comprises administering to at least one eye of the patient an ophthalmic formulation comprising a therapeutically effective amount of one or more parasympathomimetic agents, or pharmaceutically acceptable salts thereof; and a therapeutically effective amount of an alpha agonist or an alpha antagonist or a pharmaceutically acceptable salt thereof.

A method of inducing multifocal vision in a subject by miosis of the eye of a patient having at least one refractive error selected from myopia, hyperopia and astigmatism in a pseudocrystalline patient comprises administering to at least one eye of the patient an ophthalmic formulation comprising a therapeutically effective amount of one or more parasympathomimetic agents or pharmaceutically acceptable salts thereof, alone or in combination with a therapeutically effective amount of an alpha agonist or an alpha antagonist or pharmaceutically acceptable salts thereof.

A method of treating at least one refractive error in a patient having undergone eye surgery comprises administering to at least one eye of the patient an ophthalmic formulation comprising a therapeutically effective amount of one or more parasympathomimetic agents or pharmaceutically acceptable salts thereof; and a therapeutically effective amount of an alpha agonist or an alpha antagonist or a pharmaceutically acceptable salt thereof. In some embodiments, refractive errors may include, but are not limited to, myopia, hyperopia, astigmatism and any combination of myopia, hyperopia and astigmatism in pseudolenticular patients. The ocular surgery may include cataract surgery, surgery to alter at least one eye with an intraocular lens, or lens replacement.

A method of treating pseudophakic disease in a patient comprises administering to at least one eye of the patient an ophthalmic formulation comprising a therapeutically effective amount of one or more parasympathomimetic agents or pharmaceutically acceptable salts thereof; alone or in combination with a therapeutically effective amount of an alpha agonist or an alpha antagonist or a pharmaceutically acceptable salt thereof.

In some embodiments, the one or more parasympathomimetic agents is carbachol or pilocarpine, and the alpha agonist is brimonidine or phentolamine.

In some embodiments, the alpha agonist is brimonidine or a pharmaceutically acceptable salt thereof, which is present in an amount less than about 0.05%, 0.2%, 0.15%, or 0.10%. In other embodiments, the alpha antagonist is phentolamine or a pharmaceutically acceptable salt thereof, which is present in an amount of less than 2%. In some further embodiments, the one or more parasympathomimetic agents is carbachol or a pharmaceutically acceptable salt thereof, which is present in the formulation in an amount of about 0.50% to 5%. In other embodiments, the one or more parasympathomimetic agents is pilocarpine, or a pharmaceutically acceptable salt thereof, present in the formulation in an amount of about 0.25% to 1.5%. In yet other embodiments, the one or more parasympathomimetic agents is pilocarpine, or a pharmaceutically acceptable salt thereof, present in the formulation in an amount of about 0.25% to 4.0%. In other embodiments, pilocarpine, or a pharmaceutically acceptable salt thereof, is present in an amount less than 0.1%.

In some embodiments, the ophthalmic formulation comprises a penetration enhancer, such as benzalkonium chloride (BAC or BAK), in an amount from 0.005% to 0.3%. More preferably, benzalkonium chloride is present in an amount of 0.005% to 0.1%.

The use of alpha adrenergic stimulation, such as from brimonidine, when combined with topical parasympathomimetic drugs for pseudophakic disorders, can be used to improve dark and intermediate illumination vision.

Drawings

Figure 1 shows the visual acuity changes at 1, 2 and 4 hours after administration of 0.25% pilocarpine alone, 0.5% pilocarpine alone, 1.0% pilocarpine alone, 0.25% pilocarpine in combination with 0.2% brimonidine, 0.5% pilocarpine in combination with 0.2% brimonidine or 1.0% pilocarpine in combination with 0.2% brimonidine.

Figure 2 shows the mean change in visual acuity at 1, 2, 4, 8 and 10 hours post-administration for the active drug group and the placebo group. Filled squares represent the average visual acuity change for the active drug group, while filled triangles represent the average visual acuity change for the placebo group.

FIG. 3 shows the mean distribution of change in myopia acuity (Jaeger) over time for presbyopic subjects aged > 50 years (2.25% carbachol plus brimonidine vs placebo).

Figure 4 shows myopic acuity (Jaeger) over time for aged subjects <50 years of age (2.25% carbachol plus brimonidine versus placebo).

Figure 5 shows the mean distribution of change in myopia acuity (J) over time for presbyopic subjects (carbachol 2.25% plus brimonidine vs placebo vs brimonidine).

Figure 6 shows the mean distribution of change in myopia acuity (J) over time for myopic presbyopic subjects (carbachol 1.5% plus brimonidine versus placebo versus brimonidine).

Figure 7 shows the mean distribution of change in near visual acuity (J) over time for hyperopic presbyopic subjects (carbachol 3% plus brimonidine versus placebo versus brimonidine).

Figures 8a-8b show data from a study comparing 3% carbachol plus 0.2% brimonidine eye drops administered in a combined formulation to the same subject with separate administration.

Figure 9 shows the mean distribution of myopic acuity (J) over time for the same presbyopic subjects receiving 3% carbachol plus 2% brimonidine in combination and separately.

Figure 10 shows the mean distribution of pupil size (mm) over time for the same presbyopic subjects receiving 3% carbachol plus 2% brimonidine in combination and separately.

Figure 11 shows the mean distribution of myopic acuity (J) over time in all groups.

Figure 12 shows the relationship between pupil diameter change and near LogMar VA.

Figure 13 shows the change in LogMar near UCVA relative to pre-treatment baseline.

Figure 14 shows the change in carbachol plus brimonidine (0.2%) relative to baseline near LogMarVA compared to placebo.

Figure 15 shows the side effects of carbachol plus brimonidine over 7 days.

Fig. 16 shows responses to a survey on whether the patient will use drops in the future.

Figure 17 shows visual measurements of PD (pupil dilation) over time for B (brimonidine), P (pilocarpine), and PB (brimonidine plus pilocarpine).

Figure 18 shows visual measurements of NV (near vision) over time for B (brimonidine), P (pilocarpine), and PB (brimonidine plus pilocarpine).

Figure 19 shows visual measurements of IV (medium illumination vision) over time for B (brimonidine), P (pilocarpine) and PB (brimonidine plus pilocarpine).

Fig. 20 shows responses to a survey on whether the patient will use drops in the future.

Figure 21 shows data from 15 patients treated with combination drops following intraocular lens replacement.

Figure 22 shows the mean change profile over time for near visual acuity (Jaeger) for group 1 receiving 2.25% carbachol plus brimonidine relative to group 2 receiving 3% carbachol plus brimonidine.

Figure 23 shows the mean distribution of pupil size (Jaeger) over time for group 1 receiving 2.25% carbachol plus brimonidine versus group 2 receiving 3% carbachol plus brimonidine.

Figure 24 shows the mean pupil size over time for emmetropic presbyopic subjects receiving 3% carbachol plus 0.2% brimonidine drops containing a combination of 100ppm benzalkonium chloride, separately administered 3% carbachol containing 50ppm benzalkonium chloride followed by 0.2% brimonidine, administered 3% carbachol containing 50ppm benzalkonium chloride only, and administered 0.2% brimonidine containing 50ppm benzalkonium chloride only.

Figure 25 shows the average myopic acuity over time for emmetropic presbyopia for subjects receiving 3% carbachol plus 0.2% brimonidine drops containing a combination of 100ppm benzalkonium chloride, separately administered 3% carbachol containing 50ppm benzalkonium chloride followed by 0.2% brimonidine, administered 3% carbachol containing 50ppm benzalkonium chloride only, and administered 0.2% brimonidine containing 50ppm benzalkonium chloride only.

Figure 26a shows the effect of 2.25% carbachol and 0.2% brimonidine versus 3% carbachol and 0.2% brimonidine on pupil size over time.

Figure 26b shows the effect of 2.25% carbachol and 0.2% brimonidine versus 3% carbachol and 0.2% brimonidine over time on myopia acuity.

Figure 27 shows the mean change distribution of myopia acuity for the treated and control groups.

Figure 28 shows the mean pupil size distribution over time for the treated and control groups.

Detailed Description

U.S. patent No. 8,299,079 entitled "formulations and methods for improving or mitigating presbyopia" on day 10/30 in 2012 and U.S. patent No. 8,455,494 entitled "formulations and methods for improving or mitigating presbyopia" on day 6/4 in 2013; and U.S. patent publication No. 2010/0298335, "formulations and methods for improving or reducing presbyopia" published on 25/11/2010, and U.S. patent publication No. 2013/0245030, "formulations and methods for improving or reducing presbyopia" (which are incorporated herein by reference in their entirety) published on 19/9/2013, discuss methods and formulations for reducing presbyopia using parasympathomimetic drugs and alpha agonists.

In embodiments described herein, ophthalmic topical formulations are provided comprising a therapeutically effective amount of one or more parasympathomimetic agents or one or more cholinesterase inhibitors, or pharmaceutically acceptable salts thereof and one or more alpha agonists or antagonists, or pharmaceutically acceptable salts thereof.

In some embodiments, the one or more parasympathomimetic agents are pilocarpine or carbachol or a pharmaceutically acceptable salt thereof. In additional embodiments, the one or more alpha agonists are brimonidine or a pharmaceutically acceptable salt thereof. In additional embodiments, the one or more parasympathomimetic agents are replaced with a cholinesterase inhibitor.

In some embodiments, the one or more cholinesterase inhibitors is an organophosphate, such as mepiquat chloride; carbamates, such as physostigmine (also known as escin), neostigmine (also known as promos' amine), pirstigmine, amberlite, demercarine (demarcanium), or rivastigmine; phenanthrene derivatives, such as galantamine; piperidine compounds, such as donepezil, tacrine (also known as Tetrahydroaminoacridine (THA)), epxolone chloride, huperzine a or ladostigil. In another embodiment, the cholinesterase inhibitor may be fluorophosphates or DFP (isofluorophosphates). In other embodiments, the one or more cholinesterase inhibitors is iodic acid ester (also known as iodic acid ester) or physostigmine, or a pharmaceutically acceptable salt thereof.

In certain embodiments, the one or more alpha antagonists is doxazosin, silodosin, prazosin, tamsulosin, alfuzosin, terazosin, tramazosin, phenoxybenzamine or phentolamine, moxider or a pharmaceutically acceptable salt thereof.

In embodiments described herein, the pharmaceutical formulation comprises one or more parasympathomimetic agents (also known as muscarinic agonists) or cholinesterase inhibitors, alone or in combination with one or more alpha agonists. In one embodiment, the one or more parasympathomimetic agents is pilocarpine. In another embodiment, the one or more parasympathomimetic agents is carbachol. In a further embodiment, the one or more parasympathomimetic agents are pilocarpine and carbachol or pharmaceutically acceptable salts thereof. In certain embodiments, the one or more alpha agonists are brimonidine or phentolamine or a pharmaceutically acceptable salt thereof.

Ophthalmic formulations can be administered as often as necessary to subjects with myopia, hyperopia, astigmatism, presbyopia, or other optical errors to induce a miosis sufficient to temporarily treat, ameliorate or reduce these optical errors, and to temporarily create multifocal vision. These optical errors all benefit from these drugs to the extent they are clinically and practically usable, making them completely unnecessary for patients who require glasses at all times. Accordingly, the present invention also provides a method of temporarily treating, ameliorating or mitigating these optical errors by inducing a miosis and temporarily creating multiple foci.

An "optical error" or "ametropia" as defined in the present application, also referred to as ametropia (visual anomaly), is a visual defect or optical defect that prevents the eye from correctly focusing light, resulting in blurred vision. Primary refractive errors are myopia (nearsightedness), hyperopia (farsightedness, blurred vision), presbyopia (when the lens in the eye loses elasticity), pseudophakia (a defect in near vision caused by the implantation of an intraocular lens), and astigmatism (including regular, irregular, and highly regular astigmatism). Some refractive errors occur after cataract surgery or laser surgery.

As used herein, the term "parasympathomimetic agent or drug" or "muscarinic agonist" is intended to include any cholinergic agent that enhances the acetylcholine-mediated action of the central nervous system, the peripheral nervous system, or both. Examples of such so-called acetylcholine receptor agonists suitable for use in the formulations and methods of the present invention include acetylcholine, muscarinic, pilocarpine, nicotine, succinylcholine, carbamoylcholine, carbachol, methacholine, phenylpropanolamine, amphetamine, ephedrine, phentolamine and fenfluramine.

As used herein, the term "alpha agonist" or "alpha blocker" refers to a compound that preferentially stimulates alpha (both alpha 1 and alpha 2) adrenergic receptors. Examples of alpha androgen agonists suitable for use in the formulations and methods of the invention include amiloride, apraclonidine, brimonidine, clonidine (and derivatives thereof, such as p-chloro and amino derivatives), detomidine, dexmedetomidine, bipentanoyl epinephrine, guanabenz, guanfacine, isoproterenol, medetomidine, metaproterenol, mephenbutamine, methoxamine, methyldopa, naphazoline, norepinephrine, phentolamine, phenylephrine, rimenide, albuterol, terbutaline, tetrahydrozoline, xylazine, moxideril and pharmaceutically acceptable salts and prodrugs thereof.

In the present invention, a "therapeutically effective amount" is any amount of one or more active ingredients present in the formulation of the present invention that, when administered to a subject suffering from refractive error, is effective to cause a miosis sufficient to temporarily reduce, ameliorate or treat the refractive error, such that vision in the treated eye is temporarily partially or fully restored. Depending on the refractive error being treated, complete recovery of vision should be sufficient to allow the patient to read the 12 Times New Roman font at near or far distances without any other assistance. Partial recovery of near vision will allow the treated eye to see with reduced blur. Furthermore, a "therapeutically effective amount" is any amount of one or more active ingredients present in a formulation of the invention that, when administered to a subject with refractive error, is effective to cause sufficient pupillary constriction to temporarily reduce, ameliorate or treat the refractive error, such that multifocal temporary partial or complete recovery of the treated eye occurs. If a person observes a length that exceeds the focal length and the person's near vision is better than Jaeger 5 or 20/50, then multifocal vision is restored.

Thus, a therapeutically effective amount refers to an amount of the therapeutic agent that reduces the degree of refractive error by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100%. For certain embodiments, the amount of the ophthalmic formulation comprising one or more parasympathomimetic agents and one or more alpha agonists is effective to improve or reduce refractive error by about 12 hours, 11 hours, 10 hours, 9 hours, 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour. The degree of presbyopia may be determined by any method known in the art for ophthalmic examinations.

For certain embodiments, the amount of the ophthalmic formulation comprising one or more parasympathomimetic agents, alone or in combination with one or more alpha agonists, is effective to provide multifocal recovery for about 8 hours, 7 hours, 6 hours, 5 hours, 4 hours, 3 hours, 2 hours, or 1 hour.

In some of these embodiments, the parasympathomimetic agent is carbachol and the alpha agonist is brimonidine. In some embodiments, the parasympathomimetic agent is carbachol and the alpha antagonist is phentolamine. In some embodiments, the parasympathomimetic is pilocarpine and the alpha agonist is brimonidine. In some embodiments, the parasympathomimetic agent is pilocarpine and the alpha antagonist is phentolamine. In some embodiments, the concentration of carbachol is from 0.5% to 5.0%. In other embodiments, the concentration of carbachol is from 2% to 3%. In some embodiments, the concentration of pilocarpine is less than 0.1%. In some other embodiments, the pilocarpine is less than 4%. In some embodiments, the concentration of brimonidine is between 0.05% and 0.2%. In some embodiments, the concentration of phentolamine is less than 2%.

In some embodiments for treating myopic or hyperopic individuals, the concentration of carbachol is preferably about 0.5% to 5.0%. In some embodiments for treating myopic or hyperopic individuals, the concentration of carbachol is preferably about 3.0% or less. In some embodiments for treating myopia, the concentration of carbachol is preferably about 1.5% or less.

In some embodiments, brimonidine or a pharmaceutically acceptable salt thereof is present in an amount less than about 0.2%. In other exemplary embodiments, the one or more parasympathomimetic agents is pilocarpine, or a pharmaceutically acceptable salt thereof, present in the formulation in an amount less than about 0.5%. In a further exemplary embodiment, the one or more parasympathomimetic agents is pilocarpine, or a pharmaceutically acceptable salt thereof, present in the formulation in an amount less than about 0.1%.

In some further embodiments, the one or more parasympathomimetic agents is carbachol or a pharmaceutically acceptable salt thereof, which is present in the formulation in an amount of about 5%. In certain embodiments, the one or more parasympathomimetic agents is carbachol or a pharmaceutically acceptable salt thereof, which is present in the formulation in an amount of no more than 0.001%.

In some further embodiments, the one or more alpha antagonists is phentolamine or a pharmaceutically acceptable salt thereof, which is present in the formulation in an amount of no more than 2%. In certain embodiments, the one or more alpha antagonists is phentolamine or a pharmaceutically acceptable salt thereof, which is present in the formulation in an amount of no more than 0.005%.

In some embodiments, the alpha antagonist is moxider or a pharmaceutically acceptable salt thereof, which is present in the formulation in an amount of no more than 2%.

The term "ameliorating" as used in this application is intended to mean a reduction in the severity of ametropia. The improvement may be complete, e.g., complete absence of one or more refractive errors. The improvement may also be partial, such that the amount of refractive error is less than that present in the absence of treatment. For example, the degree of refractive error using the methods of the invention can be at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, or at least 100% less than the amount of refractive error present in the absence of treatment.

The methods described herein improve refractive errors, including but not limited to myopia, hyperopia, astigmatism, presbyopia, pseudophakic disorders (replacement of the natural lens with an artificial intraocular lens, e.g., after cataract surgery), and post-laser surgery deformities, by administering to at least one eye of a patient a therapeutically effective amount of an ophthalmic formulation comprising one or more parasympathomimetic agents or pharmaceutically acceptable salts thereof and one or more alpha agonists or antagonists or pharmaceutically acceptable salts thereof. In some preferred embodiments, a single ophthalmic formulation comprises a parasympathomimetic agent and an alpha agonist or antagonist. In some of these embodiments, the parasympathomimetic agent is carbachol and the alpha agonist is brimonidine. In some embodiments for treating myopic or hyperopic individuals, the concentration of carbachol is preferably about 0.5% to 5.0%. In some embodiments for treating myopic or hyperopic individuals, the concentration of carbachol is preferably about 3.0% or less. In some embodiments for treating myopic individuals, the concentration of carbachol is preferably about 1.5% or less.

Lensless cameras reduce the amount of light entering. The user need hardly focus with a lensless camera since more light is brought into more focus. The optical periphery is removed using a pinhole. The therapeutic methods and compositions described herein use drugs to achieve a pinhole effect, thereby significantly increasing the depth of focus. There are two muscles in the eye: contraction and expansion muscles. By acting on both types of muscles, the unique combination of drugs described in this application enables a pinhole effect to be achieved, correcting the refractive error.

A pharmacological pinhole effect is induced in at least the non-dominant eye of any patient with refractive error. In some embodiments, the treatment may be administered in both eyes. In some preferred embodiments, the treatment is administered only in the non-dominant eye of an emmetropic presbyopic subject and a myopic presbyopic subject and in both eyes of a hyperopic presbyopic subject and a hyperopic subject. For pure myopes, a pinhole effect may be induced in the non-dominant eye or eyes of the myope.

More specifically, parasympathomimetic compounds cause miosis (constriction), while brimonidine acts as a paralytic agent (prevents dilation). Brimonidine prevents pupil dilation that occurs at night, minimizes optical aberrations that cause halos and glare in some patients after refractive surgery, and treats glaucoma.

For some refractive errors, including but not limited to presbyopia, the formulation is placed in only one eye to reduce the likelihood of treatment-induced darkness. By placing drops in only one eye, the brain will fill in the detail obtained with the treated eye when the other eye receives light. For other refractive errors, including but not limited to hyperopia, drops are preferably placed in both eyes during treatment, but may alternatively be placed in only one eye. For patients with myopia, pseudophakia, or astigmatism, the formulation may be placed in one or both eyes.

In one embodiment, the method reduces or eliminates visual darkness of the eye of a patient, comprising administering to the eye a therapeutically effective amount of an ophthalmic formulation comprising one or more parasympathomimetic agents, or pharmaceutically acceptable salts thereof, and one or more alpha agonists or antagonists, or pharmaceutically acceptable salts thereof.

In some embodiments, the present invention relates to a method of improving the focus and/or correcting refractive error of an eye of a patient comprising administering to the eye a therapeutically effective amount of an ophthalmic formulation comprising one or more parasympathomimetic agents, or pharmaceutically acceptable salts thereof, and one or more alpha agonists or antagonists, or pharmaceutically acceptable salts thereof.

For some refractive errors, it may also be beneficial to administer the pharmaceutical formulations described herein to only a single eye of a patient. In some cases, when the composition is administered to both eyes of a patient, far vision blurring (as a result of adaptive focusing) and visual darkness (as a result of pupil constriction) may occur. When applied to only a single eye, benefits of improved presbyopia are obtained with reduced or complete relief of blurring and dullness. It was originally thought that the patient's brain would compensate between treated and untreated eyes, thereby reducing undesirable effects. Thus, when only one eye is treated, the combination of the constricted pupil and its increased depth of field in the treated eye, and the normal distance and brightness of the untreated eye, will result in the brain ignoring any monocular blur at distance or near vision. However, when the pharmaceutical formulation is applied to both eyes, the distance vision is preserved, and even parasympathomimetic drugs alone or pharmaceutically acceptable salts thereof, such as pilocarpine and carbachol, can cause myopia metastasis, induce myopia in the case of impaired distance vision, while providing increased depth of focus. The addition of an alpha 2 agonist such as brimonidine or a pharmaceutically acceptable salt thereof can prevent myopia progression and maintain distance vision when applied to both eyes.

While brimonidine is not generally used to constrict the pupil and thus enhance vision, applicants have found that it enhances the effect of pilocarpine or carbachol on the pupil. Accordingly, one embodiment of the present application is a method of improving or reducing refractive error in a patient by administering to one or both eyes of the patient a therapeutically effective amount of pilocarpine or a pharmaceutically acceptable salt thereof and an effective amount of brimonidine or a pharmaceutically acceptable salt thereof or phentolamine or a pharmaceutically acceptable salt thereof.

Another embodiment of the present application is a method of ameliorating or reducing one or more refractive errors in a patient by administering to one or both eyes of the patient a therapeutically effective amount of carbachol or pilocarpine, or a pharmaceutically acceptable salt thereof, and an effective amount of brimonidine, or a pharmaceutically acceptable salt thereof.

Brimonidine should also enhance the effect of other parasympathomimetic drugs such as acetylcholine, muscarinic, nicotine, succinylcholine, carbamoylmethylcholine, methacholine, phenylpropanolamine, amphetamine, ephedrine, phentolamine and fenfluramine on the pupil.

In some embodiments, the two agents are administered as a single combined ophthalmic formulation. In another embodiment, the two agents are formulated as two separate ophthalmic formulations and administered to the eye sequentially or simultaneously.

In embodiments of a single combined formulation of carbachol and brimonidine, the concentration of carbachol in the formulation is preferably between about 0.1% and 5.0%, and the concentration of brimonidine in the formulation is preferably about 0.20% or less. In some preferred embodiments, the brimonidine concentration is about 0.15% or less. In other preferred embodiments, the brimonidine concentration is about 0.10% or less. In some preferred embodiments, the carbachol concentration is about 3.0% or less. In some embodiments, the carbachol concentration is 5% or less. The combined preparation also preferably comprises a penetration enhancer. In some embodiments, the penetration enhancer includes, but is not limited to, one or more of carboxymethylcellulose, BAK, nanoparticles, cyclodextrin, and EDTA. In some embodiments, the combination preparation further comprises topiramate. The combination formulation is more effective in improving refractive error than carbachol and brimonidine drops administered alone.

In some embodiments, the formulation may also include penetration enhancers and excipients to improve efficacy and reduce ocular surface toxicity and improve tolerability. In some embodiments, the penetration enhancer is BAC in an amount of 0.1% to 0.3%.

In embodiments of a single combined formulation of pilocarpine and brimonidine, the concentration of pilocarpine is preferably less than 0.1% and the concentration of brimonidine in the formulation is preferably about 0.20% or less. In some preferred embodiments, the brimonidine concentration is about 0.15% or less. In other preferred embodiments, the brimonidine concentration is about 0.10% or less. In still other preferred embodiments, brimonidine is 0.05%. The combined preparation may also comprise other ingredients, such as penetration enhancers.

In embodiments of a single combined preparation of pilocarpine and phentolamine, the concentration of pilocarpine is preferably less than 0.1%. The combined preparation may also comprise further ingredients, such as penetration enhancers.

In embodiments of a single combined formulation of carbachol and phentolamine, the concentration of carbachol in the formulation is preferably from about 0.5% to 5.0%, and the concentration of phentolamine in the formulation is preferably about 2.0% or less. In some preferred embodiments, the carbachol concentration is about 3.0% or less. In some embodiments, the carbachol concentration is 5% or less. The combined preparation may also comprise other ingredients, such as penetration enhancers.

In some embodiments, the formulation for treatment comprises topiramate to alleviate symptoms of migraine. Migraine headache is usually caused by ciliary muscle spasms, which affect zonular fibers in the eye. Zonular fibers suspend the lens in place during accommodation and enable a change in lens shape for light focusing. In some embodiments, the concentration of tropicamide is about 0.01% to about 0.10% w/v. In some preferred embodiments, the concentration of tropicamide is about 0.25% to about 0.080% w/v. In other preferred embodiments, the concentration of tropicamide is about 0.04% to about 0.06% w/v.

The pharmaceutical formulations described herein are suitable for topical administration to the eye in the form of solutions, suspensions, ointments or creams. Alternatively, the ophthalmic pharmaceutical preparation may be used in the form of an eyewash, an ophthalmic solution (e.g., eye drops), or an ophthalmic ointment.

Ophthalmic pharmaceutical formulations can be prepared using commonly used pharmaceutically acceptable carriers in such a manner as to mix them with an effective amount of one or more parasympathomimetic agents and one or more alpha agonists as appropriate for the desired formulation. The carrier for the ophthalmic solution and the eye lotion includes any one of commonly used carriers, usually pure water. The ophthalmic pharmaceutical preparation may be prepared in a solution form in advance or processed into a solid preparation using a lyophilization method or the like for use in a desired preparation, for example, dissolving the solid preparation in a desired liquid carrier. Examples of such solid preparations include tablets, granules and powders. These ophthalmic pharmaceutical preparations can be prepared according to conventional methods, and should preferably be sterilized by conventional methods using a membrane filter, autoclave, or the like before use. Ophthalmic formulations may contain sugars such as glucose and maltose; sugar alcohols such as mannitol and sorbitol; electrolytes such as sodium chloride, sodium hydrogen phosphate, potassium chloride, magnesium sulfate and calcium chloride; amino acids such as glycine and alanine; vitamins and derivatives thereof such as thiamine hydrochloride, riboflavin sodium phosphate, pyridoxine hydrochloride, nicotinamide, folic acid, biotin, vitamin A, L-ascorbic acid, alpha-glycosyl-L-ascorbic acid, all of which may be used in appropriate combinations. In particular, in the case of the ophthalmic pharmaceutical preparation of the present invention in the form of an ophthalmic solution, the combined use of one or more parasympathomimetic agents and one or more alpha agonists as active ingredients and one or more other sugars selected from monosaccharides such as glucose and fructose, disaccharides such as maltose, and oligosaccharides higher than maltotriose can stably exert a satisfactory therapeutic effect. In addition, viscosity-imparting agents such as methylcellulose, carboxymethylcellulose, chondroitin sulfate, polyvinyl alcohol, and pullulan, and solubilizing agents such as polysorbate 80 may be used in the formulation.

In some preferred embodiments, penetration enhancers including, but not limited to, carboxymethylcellulose, EDTA, nanoparticles, cyclodextrins, and BAK are included in the ophthalmic pharmaceutical formulations. In some of these embodiments, only one of these promoters is used. In other embodiments, two of these promoters are used. In yet other embodiments, three of these accelerators are used. In embodiments with nanoparticles, drops are introduced into the nanoparticles to increase penetration. BAC is a quaternary ammonium compound used as an antimicrobial preservative in pharmaceutical formulations, similar to other cationic surfactants in application.

In some embodiments, a combination of 1% to 3% carbachol or a pharmaceutically acceptable salt thereof and 0.5% to 0.2% brimonidine or a pharmaceutically acceptable salt thereof is combined in particular with a penetration enhancer containing a higher concentration of benzalkonium chloride of 0.01% to 0.3%.

In some embodiments, carbachol or a pharmaceutically acceptable salt thereof is particularly combined with a penetration enhancer containing a higher concentration of benzalkonium chloride of 0.01% to 0.3%.

In some embodiments, the composition may be formulated as a substantially water-free powder, wherein the composition is reconstituted as a solution, suspension, ointment, or cream prior to use by the patient or treating physician. Some embodiments may comprise the active ingredient and other excipients, but no water. Of course, the active ingredient and/or one or more excipients may be hygroscopic and may therefore contain small amounts of water. Some embodiments comprise no more than 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% by weight of water in the composition.

The formulation may comprise from about 0.0001% to about 5% of each of the one or more parasympathomimetic agents and the one or more alpha agonists.

In one embodiment, the formulation comprises brimonidine and a parasympathomimetic agent. In one embodiment, the parasympathomimetic agent is pilocarpine. In another embodiment, the parasympathomimetic agent is carbachol. In another embodiment, the parasympathomimetic is phentermine. In another embodiment, the formulation comprises phentolamine and a parasympathomimetic agent.

In some preferred embodiments using brimonidine, the brimonidine concentration is about 0.20% or less. In other preferred embodiments where brimonidine is used, the brimonidine concentration is about 0.15% or less. In other preferred embodiments, the brimonidine concentration is about 0.10% or less. In another preferred embodiment, the brimonidine concentration is about 0.05% or less.

The one or more parasympathomimetic agents and the one or more alpha agonists may be present in the pharmaceutical formulation as pharmaceutically acceptable addition salts. Pharmaceutically acceptable salts are well known in the art and refer to the relatively non-toxic inorganic and organic acid addition salts of the compounds of the present invention. Salts may be prepared in situ during the final isolation and purification of the compounds of the invention, or by reacting the free base with a suitable organic acid alone. Examples of pharmaceutically acceptable non-toxic acid addition salts are salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipates, alginates, ascorbates, aspartates, benzenesulfonates, benzoates, bisulfates, borates, butyrates, camphorates, camphorsulfonates, citrates, cyclopentanepropionates, digluconates, dodecylsulfates, ethanesulfonates, formates, fumarates, glucoheptonates, glycerophosphates, gluconates, hemisulfates, heptanoates, hexanoates, hydroiodides, 2-hydroxyethanesulfonates, lactobionates, lactates, laurates, dodecylsulfates, malates, maleates, malonates, methanesulfonates, 2-naphthalenesulfonates, nicotinates, nitrates, oleates, oxalates, palmitates, pamoate, pectates, persulfates, 3-phenylpropionates, phosphates, picrates, salts, Pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Additional pharmaceutically acceptable salts include, where appropriate, the non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

In certain embodiments, at least one of the drugs is present in an amount less than 75% of the effective dose for which it is intended when administered alone. For example, when pilocarpine is a drug that can be present in an amount less than 75% of its dose when used alone, then pilocarpine can be present in the formulation in greater than about 3% or 4%. For example, carbachol may be 2.25% and the normally effective dose 3%, pilocarpine may be 0.5% to 1.0% and the normally effective dose 2%.

When the α 2 agonist present in the formulation is brimonidine, some embodiments may include about 0.3% or less, no more than 0.25%, no more than 0.2%, no more than 0.19%, no more than 0.18%, no more than 0.17%, no more than 0.16%, no more than 0.15%, no more than 0.14%, no more than 0.13%, no more than 0.12%, no more than 0.11%, no more than 0.1% brimonidine, no more than 0.09% brimonidine, no more than 0.08% brimonidine, no more than 0.07% brimonidine, no more than 0.06% brimonidine, or no more than 0.05% brimonidine or a pharmaceutically acceptable salt thereof.

When the alpha 2 agonist present in the formulation is moxider, some embodiments may comprise about 2% or less of moxider or a pharmaceutically acceptable salt thereof.

When the alpha 2 agonist present in the formulation is naphazoline, some embodiments may include about 0.2% or less, no more than 0.15%, no more than 0.125%, no more than 0.12%, no more than 0.11%, no more than 0.10%, no more than 0.09%, no more than 0.08%, no more than 0.07%, no more than 0.06%, no more than 0.05% naphazoline or a pharmaceutically acceptable salt thereof. In some embodiments comprising pilocarpine or a pharmaceutically acceptable salt thereof as a parasympathomimetic agent, the formulation can comprise about 4% or less, 3% or less, no more than 2.8%, no more than 2.6%, no more than 2.5%, no more than 2.3%, no more than 2.0%, no more than 1.8%, no more than 1.6%, no more than 1.5%, no more than 1.2%, no more than 1%, no more than 0.9%, no more than 0.8%, no more than 0.7%, no more than 0.6%, no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.275%, no more than 0.25%, no more than 0.225%, no more than 0.2%, no more than 0.175%, no more than 0.15%, no more than 0.125%, no more than 0.1%, no more than 0.09%, no more than 0.08%, no more than 0.07%, no more than 0.06%, no more than 0.05%, no more than 0.04%, no more than 0.03%, no more than 0.02%, no more than 0.01%, no more than 0.005%, no more than 0.0025%, no more than 0.00125%, or no more than 0.001% of pilocarpine, or a pharmaceutically acceptable salt thereof.

When the parasympathomimetic agent present in the formulation is carbachol or a pharmaceutically acceptable salt thereof, some embodiments may comprise about 5% or less, no more than 4.5%, no more than 4%, no more than 3.5%, no more than 3%, no more than 2.75%, no more than 2.5%, no more than 2.25%, no more than 2%, no more than 1.75%, no more than 1.5%, no more than 1.25%, no more than 1%, no more than 0.75%, no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.2%, or no more than 0.1% carbachol or a pharmaceutically acceptable salt thereof.

Certain embodiments may comprise phentolamine or a pharmaceutically acceptable salt thereof as an alpha antagonist. In those embodiments, the formulation may comprise about 5% or less, no more than 4%, no more than 3.5%, no more than 3%, no more than 2.5%, no more than 2%, no more than 1.8%, no more than 1.6%, no more than 1.4%, no more than 1.2%, no more than 1%, no more than 0.9%, no more than 0.8%, no more than 0.7%, no more than 0.6%, no more than 0.5%, no more than 0.4%, no more than 0.3%, no more than 0.275%, no more than 0.25%, no more than 0.225%, no more than 0.2%, no more than 0.175%, no more than 0.15%, no more than 0.125%, no more than 0.1%, no more than 0.09%, no more than 0.08%, no more than 0.07%, no more than 0.06%, no more than 0.05%, no more than 0.04%, no more than 0.03%, no more than 0.02%, no more than 0.01%, no more than 0.005%, no more than 0.0025%, no more than 0.00125%, or no more than 0.001% of phentolamine or a pharmaceutically acceptable salt thereof.

The "%" of the dose in the formulation is intended to mean weight percent, unless otherwise stated.

When "%" of monomers in a copolymer is specified, the percentage is intended to mean the molar (or repeating unit) percentage. Thus, in a copolymer, the repeat units of each monomer are counted to calculate the total number of units of each monomer present in the copolymer. For example, a copolymer of two monomers containing one monomer (e.g., monomer a) having an average (number average) of three units per another monomer (e.g., monomer B) containing seven units is referred to as comprising 30% of monomer a and 70% of monomer B.

The pharmaceutical formulation comprising one or more parasympathomimetic agents and one or more alpha agonists may be conveniently admixed with a non-toxic pharmaceutically acceptable organic carrier or a non-toxic pharmaceutically acceptable inorganic carrier. Typical pharmaceutically acceptable carriers are, for example, water, mixtures of water and water miscible solvents such as lower alkanols or aryl alkanols, vegetable oils, polyalkylene glycols, petroleum based gels, ethyl cellulose, ethyl oleate, carboxymethyl cellulose, polyvinylpyrrolidone, isopropyl myristate and other conventionally used acceptable carriers. The pharmaceutical formulations may also contain non-toxic auxiliary substances such as emulsifiers, preservatives, wetting agents, thickeners and the like, e.g., polyethylene glycols 200, 300, 400 and 600, carbowaxes 1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial components such as quaternary ammonium compounds, salts of phenylmercuric acid known to have cold sanitizing properties and to be harmless in use, thimerosal, methyl and propyl parabens, benzyl alcohol, phenylethyl alcohol, buffering components such as sodium borate, sodium acetate, gluconate buffers, and other conventional components such as sorbitan monolaurate, triethanolamine, oleate, polyoxyethylene sorbitan monopalmitate, dioctyl sodium sulfosuccinate, monothioglycerol, thiosorbitol, ethylenediamine tetraacetic acid and the like. In addition, suitable ophthalmic vehicles may be employed as carrier media for the present purpose, including conventional phosphate buffered vehicle systems, isotonic boric acid vehicles, isotonic sodium chloride vehicles, isotonic sodium borate vehicles and the like.

The pharmaceutical preparations may contain non-toxic auxiliary substances such as antibacterial ingredients which are not harmful to the human body when used, for example thimerosal, benzalkonium chloride, methyl and propyl parabens, benzyldodecylammonium bromide, benzyl alcohol or phenethyl alcohol; a buffering component, such as sodium chloride, sodium borate, sodium acetate, sodium citrate, or gluconate buffer; and other conventional ingredients such as sorbitan monolaurate, triethanolamine, polyoxyethylene sorbitan monopalmitate, ethylenediaminetetraacetic acid, etc.

The pharmaceutical formulation may include a buffering agent to maintain the pH in a therapeutically useful range of about 4.5 to 8.5. In certain embodiments, the pH is adjusted to about 5 to 8. In other embodiments, the pH is adjusted to about 6 to 7.5. In other embodiments, the pH is adjusted to about 7.3. Buffers used are those known to those skilled in the art and are not intended to be limiting, some examples being acetate, borate, carbonate, citrate and phosphate buffers. In one embodiment of the invention, boric acid is a buffer.

The pharmaceutical formulation may comprise one or more emulsifiers. As used herein, "emulsifier" facilitates the formation and/or stabilization of an emulsion. Suitable emulsifiers may be natural materials, finely divided solids or synthetic materials. The natural emulsifier may be derived from animal or plant sources. Emulsifiers of animal origin include gelatin, egg yolk, casein, lanolin or cholesterol. Those from vegetable sources include gum arabic, tragacanth gum, carrageenan (chondrus), or pectin. Plant sources, particularly from cellulose derivatives, include methylcellulose and carboxymethylcellulose to increase viscosity. Finely divided emulsifiers include bentonite, magnesium hydroxide, aluminum hydroxide or magnesium trisilicate. Synthetic reagents include anionic, cationic or nonionic reagents. Particularly useful emulsifiers are sodium lauryl sulfate, benzalkonium chloride or polyethylene glycol 400 monostearate, or any combination thereof.

The pharmaceutical formulation may comprise one or more thickening agents. As used herein, "thickening agent" refers to an agent that makes the formulation of the present invention thick or viscous in consistency. Suitable thickeners that may be used in the context of the present invention include, for example, nonionic water soluble polymers such as hydroxyethyl cellulose (under the trademark HOT < (R) >)

250 or 350 commercially available), a cationic water-soluble polymer, such as Polyquat 37 (under the trademark Polyquat @)

CN commercially available), fatty alcohol, fatty acid, anionIonic polymers and their alkali metal salts and mixtures thereof.

The pharmaceutical formulation may comprise one or more solubilizers. As used herein, the term "solubilizing agent" refers to those substances that are capable of solubilizing a solute. Representative examples of solubilizing agents useful in the context of the present invention include, but are not limited to, complex-forming solubilizing agents such as citric acid, ethylenediamine-tetraacetic acid salts, sodium metaphosphate, succinic acid, urea, cyclodextrin, polyvinylpyrrolidone, diethylammonium-orthobenzoate salts, and micelle-forming solubilizing agents, e.g.

And spans, e.g. tweens

Other solubilizers which can be used in the formulation according to the invention are, for example, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene N-alkyl ethers, N-alkylamine N-oxides, poloxamers, organic solvents such as acetone, phospholipids and cyclodextrins.

The pharmaceutical formulation may contain a mucoadhesive agent. As used herein, the term "mucoadhesive" refers to a natural or synthetic component, including macromolecules, polymers, and oligomers, or mixtures thereof, that can adhere to the mucosa of a subject. Mucoadhesive adhesion to the mucosa occurs primarily through non-covalent interactions such as hydrogen bonding and van der waals forces. Examples of mucoadhesives for use in embodiments disclosed in the present application include, but are not limited to, carbopol

Pectin, alginic acid, alginates, chitosan, hyaluronic acid, polysorbates, such as polysorbate-20, -21, -40, -60, -61, -65, -80, -81, -85; poly (ethylene glycol), such as PEG-7, -14, -16, -18, -55, -90, -100, -135, -180, -4, -240, -6, -8, -9, -10, -12, -20, or-32; oligosaccharides and polysaccharides such as tamarind seed polysaccharide, gellan gum, carrageenan, xanthan gum, gum arabic, and dextran; cellulose esters and cellulose ethers; modified fiberCellulose polymers such as carboxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl ethyl cellulose; polyether polymers and oligomers, such as polyoxyethylene; condensation products of poly (ethylene oxide) with various active hydrogen-containing compounds having long hydrophobic chains, such as aliphatic chains of about 12 to 20 carbon atoms, for example, condensation products of poly (ethylene oxide) with fatty acids, fatty alcohols, fatty amides, polyols; polyether compounds, such as poly (methyl vinyl ether), polyoxypropylene of less than 10 repeat units; polyether compounds such as block copolymers of ethylene oxide and propylene oxide; mixtures of block copolymers of ethylene oxide and propylene oxide with other excipients such as poly (vinyl alcohol); polyacrylamide; hydrolyzing polyacrylamide; poly (vinyl pyrrolidone); poly (methacrylic acid); poly (acrylic acid) or crosslinked polyacrylic acids, e.g. carbomers

I.e. homopolymers of acrylic acid crosslinked with allyl ethers of pentaerythritol, of sucrose or of propylene. In certain embodiments, the mucoadhesive agent is a polysaccharide. One polysaccharide that is particularly useful as a mucoadhesive in the embodiments disclosed herein is tamarind seed polysaccharide, which is a galactoxyloglucan extracted from the kernel of tamarind (Tamarindus Indica) and commercially available from TCI America of portland, oregon.

The pharmaceutical formulation may contain a tonicity agent to adjust the formulation to the desired isotonic range. Tonicity agents are known to those skilled in the ophthalmic art and are not intended to be limiting, some examples include glycerin, mannitol, sorbitol, sodium chloride, and other electrolytes. In one embodiment, the tonicity agent is glycerin. In another embodiment, the tonicity agent is a chloride salt. In some embodiments, the ion content is adjusted to be from about 0.5% to about 1.8%, expressed as sodium chloride equivalents. In these embodiments, the formulation may contain, in addition to the tonicity adjusting ingredient, an ophthalmically acceptable water soluble nonionic synthetic polymer having a molecular weight in the range of 300 to 250,000, and an uncharged nonionic tonicity adjusting agent.

The exact percentage of nonionic synthetic polymer used in solution will depend on the molecular weight of the polymer selected. However, it is intended that ophthalmic solutions typically have a viscosity of about 1 to about 10cps in the absence of additional viscosity enhancing agents. In certain embodiments, the ophthalmic solution has a viscosity of about 2cps to about 8cps at 23 ℃. For example, polyvinyl alcohol and polyethylene glycol are among the nonionic polymeric materials that can be incorporated into the formulations of the present invention. When polyvinyl alcohol is added to the solution, it will be present at a concentration of about 0.1% to about 5%, or even about 0.25% to about 2%, while when polyethylene glycol is used, it will comprise about 0.25% to about 3% of the solution. Such polymers are commercially available and their composition is well known to those skilled in the art.

The pharmaceutical formulation may comprise a preservative. Preservatives are used to prevent bacterial contamination in multi-use ophthalmic formulations, and examples include, without limitation, benzalkonium chloride, stable oxychloro complexes (also known as stable oxychloro complexes)

) Phenylmercuric acetate, chlorobutanol, benzyl alcohol, parabens, and thimerosal. In some embodiments, the preservative is

The pharmaceutical formulation may contain a chelating agent to improve preservative efficacy. Suitable chelating agents are those known in the art and are not intended to be limiting, edetate salts such as edetate disodium, edetate calcium disodium, edetate sodium, edetate trisodium, and edetate dipotassium are examples of useful preservatives.

The pharmaceutical preparations may be formulated as sustained release preparations in which the active ingredient is released over a period of hours. For example, stable fluid formulations for sustained release formulations may comprise a synthetic polymer comprising both hydrophilic and hydrophobic components such that the active ingredient is encapsulated or dispersed in micellar droplets.

The polymer may be a homopolymer of a monomer containing a hydrophilic side group, such as an acid group, or it may be a copolymer of different monomers, some or all of which contain a hydrophilic side group, such as an acid group. The monomer may be a vinyl monomer. The copolymer may comprise about 10% or more of monomers comprising hydrophilic side groups. In one embodiment, more than 25% by weight of the monomers contain hydrophilic side groups. In another embodiment, more than 40% by weight of the monomers contain hydrophilic side groups. In certain embodiments, 10 to 100 weight percent of the monomers comprise hydrophilic side groups and 0 to 90 percent of the monomers are hydrophobic monomers. In other embodiments, 25 to 100 weight percent of the monomers comprise hydrophilic side groups and 0 to 75 percent of the monomers are hydrophobic monomers. In further embodiments, 40 to 100 weight percent of the monomers comprise hydrophilic side groups and 0 to 60 percent of the monomers are hydrophobic monomers.

The particular choice of monomer is made in accordance with the desired solubility or dispersibility of the polymer, the desired release profile, and other properties required for a particular formulation. Although the polymers used in the present formulations are generally free of cross-linking agents and contain both hydrophilic and hydrophobic monomers, cross-linking can serve as an additional control over the properties of the polymer. For example, a small amount of trifunctional, crosslinkable monomer may be included in the monomer mixture from which the polymer is prepared. The amount of crosslinkable monomer is generally small, for example, 1 to 15 wt%, or 1 to 10 wt%. In certain embodiments, the polymer may comprise from 10% to 75% hydrophilic monomers and from 20% to 80% hydrophobic monomers. In other embodiments, the polymer may comprise from 10% to 55% hydrophilic monomers and from 30% to 60% hydrophobic monomers.

Suitable hydrophilic monomers include monomeric acids such as acrylic acid, methacrylic acid, itaconic acid, crotonic acid, vinylsulfonic acid, maleic acid, angelic acid, oleic acid or sulfoethyl a-chloro-acrylic or methacrylic acid and vinylpyrrolidone. Natural dicarboxylic acids such as maleic acid may be introduced in the form of anhydrides.

Suitable hydrophobic monomers include alkyl acrylates, alkyl methacrylates, vinyl ethers, acrylonitrile, hydroxy methacrylates, styrene, and vinyl acetate. The alkyl group in the alkyl acrylates and methacrylates typically contains 1 to 4 carbon atoms, such as ethyl, methyl or butyl, although longer chain groups containing up to 18 carbon atoms, such as lauryl, may be used. In particular when hydrophobic monomers are present, at least a portion thereof may be a proportion of from 5% to 20% by weight of plasticizing monomer. In certain embodiments, the plasticizing monomer comprises about 10% of the polymer. Suitable plasticizing monomers are long-chain esters of acrylic or methacrylic acid, for example ethylhexyl acrylate.

In certain embodiments, the polymer is a hydrophilic monomer selected from acrylic acid, vinyl pyrrolidone, methacrylic acid, and maleic anhydride and a hydrophobic monomer selected from methyl methacrylate, butyl methacrylate, lauryl methacrylate, methyl acrylate, 2-ethylhexyl acrylate, and styrene. In another embodiment, the polymer may comprise acrylic acid in the presence or absence of vinylpyrrolidone. In certain embodiments, the polymer may comprise 20% to 55% acrylic acid.

Example 1

100ml ophthalmic solution

The ingredients in this example were prepared in a conventional manner as a sterile formulation for ophthalmic solutions, with pH adjusted to about 7.3 as necessary. This example provides 60 different ophthalmic formulations.

Example 2

100ml ophthalmic solution

The ingredients in this example were prepared in a conventional manner as a sterile formulation as an ophthalmic solution, with the pH adjusted to 7.3 using a buffer solution as necessary. This example provides 80 different ophthalmic formulations.

Example 3

100ml ophthalmic solution

Composition (I)	Measurement of
		Brimonidine or a pharmaceutically acceptable salt thereof	0.1, 0.15, 0.2 or 0.25g
Phentolamine or pharmaceutically acceptable salt thereof	0.1, 0.2 or 0.4g
		Sodium chloride	0.4g
D-glucose	0.04g
		Sterilized purified water	Balance of
Total of	100ml

The ingredients in this example were prepared in a conventional manner as a sterile formulation as an ophthalmic solution, with the pH adjusted to 7.3 using a buffer solution as necessary. This example provides 12 different ophthalmic formulations.

Example 4

The effect of pilocarpine, alone or in combination with brimonidine, on the myopic acuity (VA) of patients with presbyopia was evaluated. Initially, 10 patients were selected for preliminary evaluation. One drop of a formulation comprising 0.25%, 0.5% or 1.0% pilocarpine is administered to each patient with or without administration of one drop of a formulation comprising 0.2% brimonidine. The six doses initially tested are shown in table 1.

Dose tested
	0.25% pilocarpine
0.50% pilocarpine
	1.0% pilocarpine
0.25% pilocarpine and 0.2% brimonidine
	0.5% pilocarpine and 0.2% brimonidine
1.0% pilocarpine and 0.2% brimonidine

TABLE 1

Figure 1 shows the change in visual acuity at 1 hour, 2 hours and 4 hours after administration of one of the six doses described above. Although some patients complain of burning symptoms in their eyes, it should be noted that these formulations are not optimized for patient comfort. All six doses provided some (different) initial improvement in visual acuity. However, the effect of the formulation comprising pilocarpine alone clearly disappeared rapidly, whereas the effect of the formulation comprising both drugs took longer to disappear.

To further understand the effectiveness of the formulation containing 0.5% pilocarpine and 0.2% brimonidine, the applicant conducted a double-blind, randomized clinical trial. 40 patients with presbyopia were recruited. Patients were randomized into two arms: an active drug arm and a placebo arm. Visual acuity was measured for each patient prior to receiving treatment. On day 1 of the trial, patients receiving one drop containing 0.5% pilocarpine and one drop containing 0.2% brimonidine were received in the active drug arm. The skilled artisan will recognize that the two drugs may be formulated into a composition comprising the two drugs and that a desired number of drops of the composition are applied to the eye such that the two drugs are delivered to the eye simultaneously. Patients who included the placebo arm received two drops of placebo. The patient response to treatment was examined by measuring the visual acuity of each patient at 1, 2, 4, 8 and 10 hours after treatment. The treatment was repeated for 7 days, each time with the indicated amount administered and the patient's response was examined by measuring the visual acuity of the patient at 1, 2, 4, 8 and 10 hours after treatment. Table 2, sections 1-6 list the visual acuity of the patients measured before treatment and 1, 2, 4, 8 and 10 hours after day 1 to day 7 of treatment. While some patients complain of burning symptoms in their eyes, it should be noted that these formulations are not optimized for patient comfort.

TABLE 2 part 1

TABLE 2 part 2

Figure 2 shows the mean change in visual acuity at 1, 2, 4, 8 and 10 hours post-administration for the active drug arm and the placebo arm. Filled squares represent the average visual acuity change for the active drug group, while filled triangles represent the average visual acuity change for the placebo group. As can be seen from the data, there is a drug sequel effect 8 hours after administration for the active drug arm, allowing the patient to read hours without corrective lenses.

Example 5

One study investigated the use of carbachol and alpha agonists (brimonidine) to mitigate the effects of presbyopia (Improved Presbyopic Vision With surgery, Abdelkader, Eye & Contact Lens: Science & Clinical Practice,41(5): 323-.

A prospective double-blind randomized placebo-controlled clinical trial included 48 natural emmetropic and presbyopic subjects between the ages of 43 and 56, with uncorrected hyperopic acuity for both eyes of at least 20/20, and without additional ophthalmologic disorders. Presbyopia is considered to be present if the uncorrected end point print size ≧ Jaeger (J)5 improves ≧ 1 optotype with ≧ 1.00D of lens. The subjects were divided into 2 groups. The treatment group (n ═ 30 eyes) received a single dose of 2.25% carbachol plus 0.2% brimonidine eye drops. The control group (n-18 eyes) received placebo drops. Drops were administered blindly to the non-dominant eye of all subjects. The shortest post-treatment follow-up was 3 months. The pupil size and both near and far visual acuity of the subjects were evaluated by blinded examiners under the same room illumination before and 1, 2, 4, 8 and 10 hours after treatment.

A statistically significant improvement in myopia acuity was observed in all subjects receiving carbachol plus brimonidine drops (P < 0.0001). The subject likes the treatment and if available they will use it. There was no evidence of tolerance or tachyphylaxis during the study.

The treatment groups received ophthalmic drops containing two drugs: carbachol 2.25% and brimonidine 0.2% (treatment group). Placebo eye drops were used as controls in some subjects. The pharmacological treatment of the treatment groups has a number of purposes: stimulation of parasympathetic innervation, increased depth of focus, and modulation by alpha agonists and enhancement and prolongation thereof. The objective of this study was to evaluate the efficacy of using parasympathomimetic drugs with alpha agonists to produce optically beneficial miosis to temporarily improve presbyopia by improving depth of focus in a blinded fashion.

Myopic, hyperopic and astigmatic patients with diopters above 0.25, as well as corneal, lens and vitreous opacities, pupil irregularities, unequal pupils, amblyopia, chronic common conditions and medications, will be excluded from patients who adversely interact with carbachol and brimonidine. A single dose of carbachol (2.25% Isopto carbachol, Alcon inc., Fort Worth, TX, USA) plus 0.2% brimonidine, or placebo, was administered blindly in the non-dominant eye of the subject. The subject was then instructed to use the eye drops once a day at home for 3 months.

The mean age of the treatment groups was 50.83 ± 4.57 years (range, 43-56 years); 16 males and 14 females. The mean age of the control group was 49.8 ± 3.1 years (range, 45-55 years); 8 males and 10 females. In the treatment group, the number of subjects aged 50 or older was 16, and the number of subjects aged <50 was 14. In the control group, the number of subjects aged at or above 50 was 9, and the number of subjects aged below 50 was 9. No statistically significant difference in mean age or gender was found in the two groups. Table 3 summarizes the demographics of the two groups of subjects.

Table 3: demographic data of treatment and control groups

On day 1, in the treatment group at > 50 years old (2.25% carbachol plus 0.2% brimonidine), mean Near Visual Acuity (NVA) improved significantly from J-7.68 + -1.62 before treatment to J-3 + -1.26 at 1 hour after treatment (P <0.0001), J-3.4 + -1.4 at 2 hours after treatment (P <0.0001), J-4 + -1.26 at 4 hours after treatment (P <0.0001), J-4.75 + -1.09 at 8 hours after treatment (P <0.0001) and J-5.6 + -1.3 at 10 hours after treatment (P < 0.0001).

In the <50 years old treatment group (2.25% carbachol plus 0.2% brimonidine), mean myopia acuity (NVA) improved significantly from J-6.29 ± 0.91 before treatment to J-2.5 ± 0.94 at 1 hour post-treatment (P <0.0001), J-3.14 ± 0.86 at 2 hours post-treatment (P ═ 0.0001), J-3.71 ± 0.91 at 4 hours post-treatment (P <0.0001), J-4.64 ± 0.74 at 8 hours post-treatment (P <0.0001) and J-5.29 ± 0.73 at 10 hours post-treatment (P ═ 0.0036).

No statistically significant differences in mean NVA and pupil size were found between the two age groups at any time point before and after treatment (P > 0.05).

TABLE 4

No statistically significant difference in mean NVA was found in placebo (control) at any time point before and after treatment. The data are summarized in table 4. Table 4 shows the mean change in Near Visual Acuity (NVA) (Jaeger) over time for the treatment (carbachol plus brimonidine) and control (placebo) groups. Fig. 3 and 4 show the mean change in near vision acuity (Jaeger) over time for the treated and control groups.

After 1 week, no statistically significant difference in mean NVA 2 hours after administration of drops was found between day 1 (J-3.4 ± 1.4) and day 7 (J-3 ± 0.73) for the treatment group at > 50 years (P ═ 0.29).

After 1 week, no statistically significant difference in mean NVA was found between day 1 (J-3.14 ± 0.86) and at 1 week (J-2.64 ± 0.74) 2 hours after administration of drops for the <50 year old treatment group (P ═ 0.11).

For the treatment group at > 50 years of age, no statistically significant difference in mean NVA 4 hours after administration of drops was found between day 1 (J-4 ± 1.26) and 1 month (J-3.56 ± 0.73) (P ═ 0.23).

For the <50 year old group, no statistically significant difference in mean NVA 4 hours after application of drops was found between day 1 (J-3.71 ± 0.91) and 1 month (J-3.29 ± 0.61) (P ═ 0.15).

For the treatment group at > 50 years of age, no statistically significant difference in mean NVA at 8 hours after administration of drops was found between day 1 (J-4.75 ± 1.09) and 2 months (J-4.13 ± 0.81) (P ═ 0.07).

For the <50 year old treatment group, no statistically significant difference in mean NVA at 8 hours after administration of drops was found between day 1 (J-4.64 ± 0.74) and 2 months (J-4.21 ± 0.43) (P ═ 0.07).

For the treatment group at > 50 years of age, no statistically significant difference in mean NVA was found between day 1 (J-5.6 ± 1.3) and at 3 months (J-5.13 ± 0.81) 10 hours after administration of drops (P ═ 0.2).

For the <50 year old treatment group, no statistically significant difference in mean (NVA) at 10 hours after administration of drops was found between day 1 (J-5.29 ± 0.73) and 3 months (J-4.93 ± 0.62) (P ═ 0.17).

The uncorrected hyperopic acuity for both eyes of all subjects before treatment was 20/20 and remained at 20/20 for all time periods after treatment.

All presbyopic subjects in this study who received carbachol plus brimonidine preferred this treatment and, if available, they would use it. They stopped using glasses for near vision, and were satisfied with both near and far vision. 12 of 30 subjects (40%) reported a very superior effect for the first 8 hours and then gradually diminished. The improvement in near vision during the working day was satisfactory for these subjects.

No participants in the placebo group will use placebo. All subjects receiving placebo reported that drops did not improve their near vision, so they discontinued use of drops.

No serious adverse ocular effects were observed during the study in the carbachol plus brimonidine treatment group. No redness or redness of conjunctiva was observed. A slight burning sensation was noted in one subject (3.3%). A mild headache was reported in 10% of all subjects. The drops show excellent safety and stability. One subject (3.3%) reported a temporary blurring of the first few weeks. However, the subject reported that the symptoms were mild and transient, and did not cause him to stop the drops. No systemic side effects such as bradycardia, bronchospasm and digestive problems were observed. There was no evidence of tolerance or tachyphylaxis, and the effect of drops persisted throughout the follow-up period.

For the placebo group, a mild burning sensation was reported in 2 subjects (11.1%).

This example uses 2.25% carbachol and an alpha agonist (0.2% brimonidine) to improve vision in presbyopia by increasing the depth of focus in participants in their four and five decades of age. The increased depth of focus allows many presbyopic subjects to benefit from the use of drops. Both of these drugs have been FDA approved and have been used safely and effectively in glaucoma for many years. Placebo drops were used as controls. This technique is believed to produce a pinhole effect that pharmacologically increases the depth of focus of the smaller pupil. In monocular therapy, the contralateral eye with a normal pupil has slightly blurred near vision, but distant objects are sharp and the perception of light is not diminished. When the images were combined, all subjects (except one) of the treatment group had clear focus, with no perception of darkness, both near and far, except one subject (3.3%). Treating only one eye does not cause the symptoms of darkness because the brain fills in brightness from the other eye. Carbachol and brimonidine can be used once daily to achieve a 10 hour effect. Brimonidine has little effect on photopic pupils, but has been effective for many years in preventing over-dilation of the pupil in the dark, thereby alleviating the scotopic symptoms typically from the peripheral cornea after refractive surgery. It has not been used to improve presbyopia.

The synergy between carbachol and brimonidine is such that a single drop application can produce a miosis sufficient to improve near vision, which is sufficient for most people over the course of a day. The combination of carbachol and brimonidine was effective and its effect was longer lasting. All subjects maintained distance vision and therefore were not reported as monocular vision symptoms. Treatment of only one eye minimizes the symptoms of darkness; the synergy allows for lower doses of miotics and relief of headache symptoms, while brimonidine eliminates any tendency of parasympathomimetics to cause hyperemia. In this study, there was no evidence of tolerance or tachyphylaxis, and the effect of drops (carbachol plus brimonidine) persists during the study. No ocular complications were detected in any of the treated eyes throughout the follow-up period. While near vision acuity improved significantly, the near vision in most subjects did not return to J1. NVA recovered to J1 in 4 subjects (13.3%) in the study group, 2 subjects per age group.

Daily treatment of presbyopia with one drop of carbachol and brimonidine in the non-dominant eye allows many presbyopic subjects, even elderly subjects, to have acceptable reading vision. The distance or intermediate vision is not blurred as typical monocular vision therapy due to the increased depth of focus of the smaller pupil, and the normal brightness perception of the untreated eye eliminates the darkening symptoms caused by the smaller pupil of the treated eye. This positive combination will also improve low non-presbyopic hyperopia and may be used with eyeglasses if necessary.

Example 6

Another study evaluated the efficacy of carbachol and brimonidine in improving vision in presbyopia, myopia and hyperopia.

The drug treatment in this study was designed to improve vision in patients with refractive errors using eye drops containing two drugs: different concentrations of parasympathomimetic (carbachol) and alpha agonist (0.2% brimonidine). Some subjects used 0.2% bromomonidine and placebo eye drops alone as controls. The pharmacological treatment of the treatment group stimulates parasympathetic innervation mainly by improving the depth of focus and possibly the modulation caused by alpha agonists and their enhancement and prolongation. The study evaluated the efficacy of using different concentrations of parasympathomimetic agents and alpha agonists to produce optically beneficial miosis for the temporary treatment of different types of presbyopia (emmetropia, myopia and hyperopia) in a blinded study.

177 presbyopic subjects were enrolled in the study, with a mean age of 49.8 ± 3.9 years (range 41-57 years); 96 males and 81 females. The study participants gave written informed consent. Pharmacological stimulation protocols were developed according to the method disclosed in U.S. patent No. 8,299,079, which is incorporated herein by reference. All subjects were in good physical and ocular health and completed a questionnaire to determine any involved contraindications or pre-disposition complications (e.g. cardiac or respiratory disorders, migraine, high myopia, ocular or systemic medication or ocular surgery). All subjects performed a comprehensive mydriatic fundus examination before being considered eligible for the study. The screening is for drug contraindications, susceptibility to retinal detachment, ophthalmic disorders or peripheral retinal degeneration. Exclusion criteria involved patients with myopia or astigmatism of greater than 0.75 diopters, and hyperopia of greater than 2 diopters in either eye, as well as patients with corneal, lens and vitreous opacities, irregular pupils, unequal pupils, amblyopia, chronic common conditions, and medications that would adversely interact with carbachol and brimonidine. Screening subjects for known sensitivity to drugs or conditions that prevent the use of these drops. During this study, subjects were closely monitored and asked to report any ocular, systemic or physiological responses they experienced on a regular basis. Atropine can be used when adverse reactions occur, but no adverse reactions are reported. Different groups of presbyopic subjects were distinguished. The first group included 66 emmetropic presbyopic subjects (n 66 eyes), the second group included 55 myopic presbyopic subjects (≦ -0.75D sphere, n 55 eyes), and the third group included 56 hyperopic presbyopic subjects (≦ +2D sphere, n 112 eyes). Each group was then subdivided by age into 50 years or over 50 years and under 50 years.

Single doses of different concentrations of carbachol (Isopto carbachol 2.25%, 1.5%, 3%, Alcon inc., Fort Worth, TX, USA) plus 0.2% bromomonidine or 0.2% bromomonidine alone or placebo were instilled blindly in the non-dominant eye of groups 1 and 2 and in both eyes of group 3, respectively. Initial pupil size and both near and far vision were recorded under the same room illumination before and 1, 2, 4, 8 and 10 hours after treatment. Subjects were monitored and comprehensive ocular examinations, including visual acuity assessment and slit lamp biopsy, were performed one week after treatment and every month for the first three months to assess dose, satisfaction, side effects and complications (e.g., retinal detachment, pigment dispersion, posterior adhesions, and intraocular inflammation). During the follow-up period, subjects were instructed to use eye drops once a day. Hyperopic acuity was measured using a standard snellen projection chart. The Jaeger eye chart is used to measure near visual acuity. Any adverse symptoms and the subject's satisfaction with near and far vision were also monitored.

Statistical analysis was performed using student's t-test, and p-values less than 0.05 were considered statistically significant. Data are presented as mean, range and Standard Deviation (SD).

The average subject age (age) for emmetropic presbyopic subjects (group 1) was 50.3 + -4 (range 43-57), myopic presbyopic subjects (group 2) was 50.8 + -3.7 (range 45-57), and hyperopic presbyopic subjects (group 3) was 48.3 + -3.8 (range 41-56). In group 1, the number of subjects aged > 50 was 34 and the number of subjects <50 was 32. In group 2, the number of subjects aged > 50 was 28 and the number of subjects <50 was 27. In group 3, the number of subjects aged > 50 was 29 and the number of subjects <50 was 27. No statistically significant difference in mean age or gender was found between the 3 groups.

Figures 5, 6 and 7 show the mean change in near acuity (J) over time for the emmetropic, myopic and hyperopic presbyopic groups.

Group 1 (emmetropic presbyopic subject):

the concentration of carbachol used in this group was 2.25%. The mean pre-treatment manifest refraction was-0.1. + -. 0.12D. The mean post-treatment refraction at 1, 2, 4, 8, 10 hours was-0.6 + -0.14D, -0.5 + -0.12D, -0.48 + -0.09D, -0.4 + -0.1D, and-0.38 + -0.12D, respectively.

As shown in table 5, in the treatment group at > 50 years old (carbachol 2.25% plus brimonidine 0.2%), the mean Near Visual Acuity (NVA) increased significantly from J-7.6 ± 1.62 before treatment to J-3 ± 1.26 at 1 hour after treatment (P <0.0001), J-3.4 ± 1.4 at 2 hours after treatment (P <0.0001), J-4 ± 1.26 at 4 hours after treatment (P <0.0001), J-4.75 ± 1.09 at 8 hours after treatment (P <0.0001) and J-5.6 ± 1.3 at 10 hours after treatment (P ═ 0.00004).

Table 5: group 1 (presbyopic subjects) is more than or equal to 50 years old

2.25% carbachol plus brimonidine vs placebo vs brimonidine

As shown in table 6, in the <50 years old treatment group (carbachol 2.25% plus brimonidine 0.2%), the mean Near Visual Acuity (NVA) increased significantly from J-6.29 ± 0.91 before treatment to J-2.5 ± 0.94 at 1 hour after treatment (P <0.0001), J-3.14 ± 0.86 at 2 hours after treatment (P ═ 0.0001), J-3.71 ± 0.91 at 4 hours after treatment (P <0.0001), J-4.64 ± 0.74 at 8 hours after treatment (P <0.0001) and J-5.29 ± 0.73 at 10 hours after treatment (P ═ 0.0036).

Table 6: group 1 (presbyopic subjects) <50 years old

2.25% carbachol plus brimonidine 0.2% eye drops versus placebo versus brimonidine

No statistically significant difference in mean NVA was found between groups > 50 and <50 at pre-treatment (P ═ 0.5) and post-treatment 1 hour (P ═ 0.49), post-treatment 2 hours (P ═ 0.7), post-treatment 4 hours (P ═ 0.64), post-treatment 8 hours (P ═ 0.94) and post-treatment 10 hours (P ═ 0.57).

No statistically significant difference in mean NVA was found in the placebo group or the 0.2% brimonidine group alone at any time point before and after treatment.

Group 2 (myopic presbyopic):

the concentration of carbachol used in this group was 1.5%. Before the average treatment, the ametropia of the spherical lens is-0.63 +/-0.13 diopter, and the average refractive astigmatism reaches 0.17 +/-0.24 diopter. The average treatment rear sphere diopter at 1, 2, 4, 8 and 10 hours is-0.8 +/-0.18D, -0.71 +/-0.22D, -0.69 +/-0.21D, -0.67 +/-0.23D and-0.65 +/-0.18D respectively.

As shown in Table 7, in the treatment group at > 50 years old (carbachol 1.5% plus brimonidine 0.2%), the mean near visual acuity NVA increased significantly from J-5.5 + -1.37 before treatment to J-2.25 + -0.58 (P <0.0001) at 1 hour after treatment, J-2.75 + -0.58 (P <0.0001) at 2 hours after treatment, J-3.13 + -0.72 (P <0.0001) at 4 hours after treatment, J-3.25 + -0.68 (P <0.0001) at 8 hours after treatment, and J-3.63 + -0.89 (P <0.0001) at 10 hours after treatment.

Table 7: group 2 (myopia presbyopia) is more than or equal to 50 years old

1.5% carbachol plus brimonidine vs placebo vs brimonidine

As shown in table 8, in the <50 years old treatment group (carbachol 1.5% plus brimonidine 0.2%), the mean myopia acuity (NVA) increased significantly from J-5.86 ± 0.7 before treatment to J-2 ± 0.55 at 1 hour after treatment (P <0.0001), J-2.57 ± 1.1 at 2 hours after treatment (P ═ 0.0001), J-2.86 ± 0.86 at 4 hours after treatment (P <0.0001), J-3.29 ± 0.9 at 8 hours after treatment (P <0.0001) and J-3.86 ± 0.86 at 10 hours after treatment (P ═ 0.0002).

Table 8: group 2 (myopic presbyopic patient) <50 years old

1.5% carbachol plus brimonidine vs placebo vs brimonidine

No statistically significant difference in mean NVA was found between groups > 50 and <50 at pre-treatment (P ═ 0.6) and post-treatment 1 hour (P ═ 0.6), post-treatment 2 hours (P ═ 0.7), post-treatment 4 hours (P ═ 0.59), post-treatment 8 hours (P ═ 0.9) and post-treatment 10 hours (P ═ 0.54).

No statistically significant difference in mean NVA was found in the placebo group or the 0.2% brimonidine group alone at any time point before and after treatment.

Group 3 (hyperopic presbyopic):

the concentration of carbachol used in this group was 3%. The mean sphere refractive error of both eyes before treatment is +1.16 + -0.43 diopter, and the mean refractive astigmatism is 0.2 + -0.25 diopter. The average post-treatment sphere diopters of both eyes are +0.21 + -0.16D, +0.24 + -0.17D, +0.33 + -0.14D, +0.41 + -0.15D, +0.43 + -0.16D at 1, 2, 4, 8, 10 hours, respectively.

As shown in table 9, in the treatment group at > 50 years old (carbachol 3% plus brimonidine 0.2%), mean Near Visual Acuity (NVA) was significantly improved from J-7.5 ± 1.86 before treatment to J-4 ± 1.26(P <0.0001) at 1 hour after treatment, J-4.75 ± 1.18(P <0.0001) at 2 hours after treatment, J-5.38 ± 1.09(P ═ 0.0004) at 4 hours after treatment, J-5.5 ± 0.89(P ═ 0.0005) at 8 hours after treatment, and J-5.69 ± 0.79(P ═ 0.0012) at 10 hours after treatment in both eyes.

Table 9: group 3 (hyperopic presbyopic subjects) are more than or equal to 50 years old

3% carbachol plus brimonidine vs placebo vs brimonidine

As shown in Table 10, in the <50 years old treatment group (carbachol 3% plus brimonidine 0.2%), the mean Near Visual Acuity (NVA) of both eyes increased significantly from J-7.29 + -1.2 before treatment to J-3 + -1.36 (P <0.0001) at 1 hour after treatment, J-4.29 + -1 (P <0.0001) at 2 hours after treatment, J-4.57 + -1.2 (P <0.0001) at 4 hours after treatment, J-4.86 + -1.17 (P <0.0001) at 8 hours after treatment, and J-5 + -1.36 (P <0.0001) at 10 hours after treatment.

Table 10: group 3 (hyperopic presbyope) <50 years old

3% carbachol and brimonidine eye drops versus placebo versus brimonidine

No statistically significant difference in mean NVA was found between groups > 50 and <50 at pre-treatment (P ═ 0.8) and post-treatment 1 hour (P ═ 0.2), post-treatment 2 hours (P ═ 0.4), post-treatment 4 hours (P ═ 0.2), post-treatment 8 hours (P ═ 0.3) and post-treatment 10 hours (P ═ 0.27).

The best corrected distance visual acuity for both eyes was 20/20 for all subjects before treatment and remained 20/20 for all time periods after treatment.

No statistically significant difference in mean NVA was found in the placebo group or the 0.2% brimonidine group alone at any time point before and after treatment.

All emmetropic and myopic presbyopic subjects who received carbachol plus brimonidine forgo to use glasses. No one will use placebo or brimonidine drops alone. All subjects reported that drops did not improve their near vision, so they stopped using drops.

24 of 30 hyperopic presbyopic subjects given carbachol plus brimonidine drops (80%) gave up using glasses for far and near vision. Four subjects (13.4%) used glasses for near vision only, with a diopter 2 to 3 lower than that required before treatment according to their original distance vision. Only two subjects (6.6%) dropped treatment. They show that glasses will provide them with better near vision. No one will use placebo or brimonidine drops alone because all subjects did not feel the difference and stopped using drops.

No serious ocular adverse reactions were observed in participants treated with carbachol plus brimonidine drops during the study. A slight burning sensation was noted in 5.5% of all groups. Blunt-headed pain and migraine were reported in 10% of all subjects on the first few days. All groups reported temporary difficulties in low brightness for the first few weeks, but more commonly (40%) in hyperopic subjects. However, these subjects reported that these symptoms were mild and transient, and did not result in their discontinuation of drops. 97.8% of the treated subjects in all groups indicated that they would use drops to treat their presbyopia. They were satisfied with both near and far vision. The drops show excellent safety and stability. There was no evidence of tolerance or tachyphylaxis, and the effect of drops persisted throughout the follow-up period.

Mild burning was reported in 10 subjects receiving brimonidine drops. No adverse symptoms were reported by the placebo group.

In blinded studies, 100% of subjects in groups 1 and 2 liked carbachol plus brimonidine drops and, if available, carbachol plus brimonidine drops would be used. In group 3, 80% of subjects abandoned the use of glasses, 13.4% of subjects abandoned the use of glasses for near vision only, and 2 to 3, 6.6% of subjects abandoned the treatment, with a diopter lower than that required before the treatment according to their original distance vision. No one will use placebo or brimonidine alone. There was no evidence of tolerance or tachyphylaxis during follow-up.

Carbachol plus brimonidine appears to be an acceptable and safe alternative to corrective lenses and surgery.

As described above, the study used varying concentrations of carbachol and alpha agonist (0.2% brimonidine) to improve vision in participants with refractive errors. Either placebo or brimonidine drops alone were used as controls. This technique is based on the pharmacological generation of a pinhole effect, increasing the depth of focus from the smaller pupil, and making the vision produced in the eye clear. With monocular treatment, the vision of the contralateral eye with a normal pupil may have slightly blurry near vision, but distant objects are sharp and light perception is not diminished. When the images were combined, most subjects in groups 1 and 2 had clear focus at both near and far distances, with no perception of darkness. In group 3, 40% of subjects reported transient dimming within the first few weeks. This is due to bilateral treatment and the use of higher concentrations of carbachol (3%) in these eyes. However, these subjects reported that these symptoms were mild and transient, and did not result in their discontinuation of drops.

Carbachol and brimonidine can be used once daily to achieve a 10 hour effect. Brimonidine has little effect on photopic pupils, but has been effective for many years in preventing over-dilation of the pupil in the dark, thereby alleviating the scotopic symptoms typically from the peripheral cornea after refractive surgery. The study found that carbachol and brimonidine had a synergistic effect in treating presbyopia and myopia and hyperopia. Distance vision is preserved, so there is no monocular vision symptoms; treatment of only one eye in some participants can minimize the symptoms of darkness; the synergy permits the use of lower doses of miotics and alleviates headache symptoms, and brimonidine eliminates any tendency of parasympathomimetics to cause hyperemia.

In this study, there was no evidence of tolerance or tachyphylaxis, and the effect of drops (carbachol plus brimonidine) persisted over a three month treatment period. No ocular complications were detected in any of the treated eyes throughout the follow-up period.

The use of carbachol and brimonidine for the pharmacological treatment of refractive errors including presbyopia, myopia and hyperopia is an acceptable and safe alternative to spectacles and monofocal or multifocal contact lenses or any other surgical option. The combination of carbachol and brimonidine can improve reading vision in many presbyopic subjects. This study showed that carbachol and brimonidine improved conventional distance vision and reading, and that the patient no longer required glasses that had to be worn all the time before. Thus, this combination treatment may also improve low-grade non-presbyopic hyperopia and myopia. The treatment may also be used to treat other refractive problems. This possibility of drug treatment opens up a new treatment for subjects with refractive errors, enabling them to adapt well over time.

Pilocarpine and brimonidine similarly can treat refractive errors, including presbyopia, myopia, and hyperopia.

Example 7

This study compared the efficacy of a formulation comprising both carbachol and brimonidine with separate carbachol and brimonidine formulations administered simultaneously. The same participants received both the combination and the individual formulations with a one week washout period between administrations.

This study tested and compared the effectiveness of using a parasympathomimetic drug (3% carbachol) and an alpha agonist (0.2% brimonidine) in combination and separately in a blinded study to produce optically beneficial miosis to pharmacologically improve presbyopic vision.

A prospective blind randomized clinical trial employed 10 natural emmetropic and presbyopic subjects aged between 42 and 58 years of age, with uncorrected hyperopic acuity for both eyes of at least 20/20 and without additional ocular disorders. Participants were volunteers selected at random. Presbyopia is considered to be present if the uncorrected end point print size ≧ Jaeger (J)5 improves ≧ 1 optotype with ≧ 1.00D of lens. All subjects were in good physical and ocular health and completed a questionnaire to determine any involved contraindications or pre-disposition complications (e.g. cardiac or respiratory disorders, migraine, high myopia, ocular or systemic medication or ocular surgery). All subjects performed a comprehensive mydriatic fundus examination before being considered eligible for the study. The screening test is carried out for drug contraindications, susceptibility to retinal detachment, ophthalmological disorders or peripheral retinal degeneration.

Inclusion criteria included age between 41 and 60 years, presbyopia (uncorrected end point print size ≧ jaeger (j)5, improvement ≧ 1 optotype in the case of using ≧ 1.00D lenses), emmetropia (mydriatic sphere power (SE), ± 0.25D; astigmatism ≦ 0.25D), and uncorrected hyperopic acuity ≧ 20/20 for both eyes. Exclusion criteria included patients with myopia, hyperopia and astigmatism above 0.25 diopters, as well as patients with corneal, lens and vitreous opacities, irregular pupils, unequal pupils, amblyopia, chronic common conditions, and medications that would adversely interact with carbachol and brimonidine.

All subjects received single doses of 3% carbachol and 0.2% brimonidine in their non-dominant eye in a crossover fashion, with a one week washout period between tests. In a separate form, carbachol is administered first, followed by brimonidine after 5 minutes. Subjects were evaluated for pupil size and both near and far vision under the same room illumination by blinded examiners before and 1, 2, 4 and 8 hours after treatment. In addition, all subjects received only a single dose of 3% carbachol or only a dose of 0.2% brimonidine. Figures 8a-8b show data from the study. All subjects were monitored to assess dose, satisfaction, adverse reactions and complications.

The study used a standard snellen projection chart to measure distance visual acuity. Myopia acuity was assessed at 40cm using a jaeger (j) visual chart. Statistical analysis was performed using student's t-test, and p-values less than 0.05 were considered statistically significant. Data are presented as mean, range and Standard Deviation (SD).

Figure 9 shows the mean distribution of myopic acuity (J) over time for the same presbyopic subjects receiving 3% carbachol plus 2% brimonidine in combination and separately. When the combination drops were administered to participants, the average change between NVA before and immediately after treatment was much greater. The change continued to be greater with administration of the combined drops throughout the eight hour data collection period.

Figure 10 shows the mean distribution of pupil size (mm) over time for the same presbyopic subjects receiving 3% carbachol plus 2% brimonidine in combination and separately. When the combination drops were administered to participants, the mean change between pupil size before and immediately after treatment was much greater. The mean change continued to be greater with administration of the combination drops throughout the eight hour data collection period.

Figure 11 shows a comparison of the distribution over time of the mean change in myopia acuity (J) between combined drops, separately administered drops, brimonidine alone and carbachol alone. The mean change was minimal for participants treated with brimonidine alone, and maximal for patients treated with combination drops.

The combination drops have a synergistic effect, improving the myopia acuity better than carbachol and brimonidine administered separately.

Example 8

Dose range studies were performed on carbachol and pilocarpine. The concentrations of pilocarpine of 0.5% and 1% were compared to pilocarpine containing brimonidine 0.2% and placebo. Carbachol concentrations of 1.5%, 2.25%, and 3% were compared to 0.2% with brimonidine and placebo. Pilocarpine and carbachol with and without brimonidine were also compared to each other.

12 subjects in group 1 were given 0.5% pilocarpine plus brimonidine 0.2%, 1.0% pilocarpine plus brimonidine 0.2%, or placebo eye drops in their non-dominant eye in a blinded fashion.

The 12 subjects in group 2 were given one of three concentrations of carbachol (1.5%, 2.25% or 3%) alone or in combination with 0.2% brimonidine or placebo eye drops in their non-dominant eye in a blinded fashion.

Both group 1 and group 2 received the same pre-and post-treatment examinations and measurements: age, gender, initial pupil size and Near Vision Acuity (NVA) were recorded. NVA of the subject was measured at 1, 2, 4 and 8 hours after treatment under the same room lighting conditions. Any adverse symptoms and subject satisfaction with near and far vision were recorded.

78 patients were evaluated in 3 centers for 0.5% pilocarpine plus 0.2% brimonidine or carbachol plus 0.2% brimonidine. 32 patients received an assessment of pilocarpine plus brimonidine, and 46 received an assessment of carbachol and brimonidine.

As shown in figures 12 and 13, there was a clear relationship between the change in pupil diameter from baseline and the change in vision in the pilocarpine plus brimonidine and pilocarpine groups. LogMAR activity was improved in patients treated with pilocarpine or carbachol plus brimonidine. The change in LogMAR VA favors pilocarpine at 1 and 2 hours. The change in LogMAR VA favors carbachol at 8 and 10 hours.

For the carbachol plus brimonidine combination, 40 patients were evaluated (placebo: N ═ 17, carbachol 1.5% + brimonidine: N ═ 8, carbachol 2.25% + brimonidine: N ═ 8, carbachol 3% + brimonidine: N ═ 7). When added to brimonidine, a dose response of carbachol was observed, as shown in figure 14. An inverse dose response to carbachol tolerance was observed, as shown in figure 15. The post-treatment satisfaction survey results for carbachol patients are shown in figure 16. The survey asks whether the patient will use drops again.

The results of these studies indicate that brimonidine has a synergistic effect with both carbachol and pilocarpine. Pilocarpine and carbachol have also been shown to be effective treatments. The combination of brimonidine and carbachol was more active and longer lasting than brimonidine and pilocarpine. Pupil size is directly related to near vision improvement. The combination significantly improves reading vision. Treatment did not cause dim symptoms because the other eye filled the brightness. The treatment does not interfere the far vision or the middle vision, and can not cause the symptoms of monocular vision. If the improved visual acuity is not sufficient to accomplish a particular task, the treatment may be used with glasses. Although pilocarpine had a more rapid effect, carbachol lasted 8 hours. An increase in carbachol concentration causes a slight increase in discomfort. Pilocarpine is unstable at neutral pH (about pH 5 is required), has a burning sensation, and is short in duration.

No significant adverse events occurred. Mild drop-related discomfort was noted in 10-30% of all groups (including placebo). 90% of subjects indicated that they would use active drops to treat their presbyopia if available.

Although 0.2% brimonidine concentration was used in this study, 0.15% or 0.1% or even lower should provide sufficient synergy with pilocarpine or carbachol. Lower concentrations of brimonidine have been shown to have a "whitening" effect on the eye. All carbachol concentrations in the study (1.5%, 2.25% and 3.0%) resulted in improved vision.

Example 9

Another study used pilocarpine in combination with brimonidine to make one pupil smaller for hours without surgery, relieve presbyopia and improve optical errors without wearing glasses.

Male and female participants of any race 45 to 60 years of age with a sphere +/-0.5D and a reading correction of +/-0.5D were selected for inclusion. Individuals allergic or having adverse reactions to pilocarpine or brimonidine, individuals with glaucoma, cataracts, eye infections, eye inflammation, retinal tears, retinal disease, individuals who had undergone ophthalmic surgery within the last 30 days, individuals who were wearing contact lenses, individuals who had been using any eye drops within the last 7 days, individuals who were pregnant or lactating, and individuals who had participated in any other clinical trial within the last 30 days were excluded from the study.

A study was conducted on 20 volunteers on 3 days separated at 1 week intervals to allow clearance. A conventional prescription of external inspection and distance and reading is also performed (these values are used if the current prescription has been determined not more than 60 days ago). Intraocular pressure (Goldman flattening) was also measured, as well as mydriasis of the lens and retina.

There were 3 study days. Each of 5 patients in 3 groups received different study medications daily. After 7 days of washout, the study was repeated on these groups using another test drug, so that each patient received the test for each drug and each patient was their own control 3 days after the study. Each patient was studied by the same examiner in the same room with the same room lighting each time they were studied.

After determining the non-dominant eye of the volunteer, the volunteer was randomly divided into 3 groups and treated with drops only in the non-dominant eye. The doses tested were: 1% pilocarpine, 0.2% brimonidine, and 1% pilocarpine plus 0.2% brimonidine. For combination eye drops, pilocarpine is administered first, followed 5 minutes later by brimonidine. Only one drop at a time was applied each. The patient was asked to read the eye chart under intermediate illumination every hour and pupil diameter was measured using an infrared pupillometer each time for 8 hours.

The results are shown in FIGS. 17-19. These figures show the visual measurements of pupil dilation, near vision, and intermediate vision over time for brimonidine alone, pilocarpine alone, and 1% pilocarpine plus 0.2% brimonidine, respectively. Both near and intermediate vision were significantly improved with pilocarpine plus brimonidine drops compared to brimonidine alone or pilocarpine alone.

These 20 patients were investigated after receiving pilocarpine plus brimonidine treatment. More specifically, they are asked if these drops are available they will replace the glasses with them. 90% of the subjects indicated that they would use the drops to treat presbyopia if available, as shown in figure 20.

Example 10

Another study tested patients who implanted an intraocular lens (IOL) (pseudolens) in the eye and required presbyopia after surgery. Patients typically undergo this type of surgery to treat cataracts and correct distant vision.

In this study, 15 patients aged 38 to 80 years received pseudophakic surgery to correct their distance vision. One patient underwent binocular surgery, and the remaining 14 patients underwent monocular surgery.

At least three months after the orthokeratology procedure, a single combination eye drop comprising 3% carbachol plus 0.2% brimonidine was administered to one eye of a presbyopic patient. The results are shown in FIG. 21.

For all patients, their distance vision before and after administration of the drops was 20/20. In all patients, their pupil size decreased significantly after treatment with drops. Furthermore, their near vision was greatly enhanced after treatment with drops during the entire eight hours after application of the drops. Only one patient reported burning side effects.

This study showed that correction of refractive errors caused by pseudomorphosis by a combined formulation of carbachol and brimonidine lasted at least 8 hours. These drops may still function to correct the myopia of these patients despite the surgical and pharmaceutical procedures performed during the procedure. Ophthalmic formulations in the form of eye drops allow many of the elderly cataract patients to be seen without presbyopic glasses.

All patent and non-patent references discussed in this application are incorporated by reference into this application.

TABLE 11

Example 11

One Study examined the effect of using Carbachol with an alpha agonist (brimonidine) on the Outcome of Presbyopia Treatment (Influence of differential considerations of Carbachol Drops on the outer of Presbyopia Treatment-A randomised Study, Abdelkader, International Journal of opthalmic Research 2019 months; 5(1): 317) 320, which is incorporated herein by reference). The aim of this study was to study the optimal dose of carbachol to effectively improve near vision in presbyopic subjects over a longer duration.

A prospective double-blind randomized study included 57 emmetropic and presbyopic subjects aged between 44 and 60 years, with uncorrected hyperopic acuity for both eyes of at least 20/20, and without additional ophthalmologic disorders. Presbyopia is considered to be present if the uncorrected end point print size ≧ Jaeger (J)5 improves ≧ 1 optotype with ≧ 1.00D of lens. The subjects were divided into 2 groups. Group 1 (n ═ 32 eyes) received a single dose of 2.25% carbachol plus 0.2% brimonidine eye drops. Group 2 (n ═ 25 eyes) received a single dose of 3% carbachol plus 0.2% brimonidine eye drops. Drops were administered to the non-dominant eye of all subjects. Subjects were evaluated for pupil size and both near and far vision by blinded examiners under the same room lighting before and 1, 2, 4, 8, and 12 hours after treatment.

A statistically significant improvement in Near Vision Acuity (NVA) (P <0.0001) was observed in all subjects receiving both concentrations of carbachol plus brimonidine drops. Higher concentrations of carbachol drops reported a significant and sustained improvement in mean NVA compared to lower concentrations (P < 0.0001). No serious ocular adverse effects were observed in any of the subjects in either group. Carbachol was found to be safe at higher concentrations and to provide greater efficacy in improving myopia acuity than lower concentrations, with a longer duration of action.

Myopic, hyperopic and astigmatic patients with diopters above 0.25, as well as corneal, lens and vitreous opacities, pupil irregularities, unequal pupils, amblyopia, chronic common conditions and medications, will be excluded from patients who adversely interact with carbachol and brimonidine.

Group 1 (2.25% carbachol) had a mean age of 51.1 ± 4.5 years (range, 44-55 years); 18 males and 14 females. Group 2 (3% carbachol) had a mean age of 52.8 ± 3.9 years (range, 47-60 years); 14 males and 11 females. In the treatment group, the number of subjects aged 50 or older was 16, and the number of subjects aged <50 was 14. No statistically significant difference in the mean age or gender of the two groups was found.

In group 1, mean Near Visual Acuity (NVA) improved significantly from J7.37 ± 1.6 before treatment to J2.96 ± 0.8 at 1 hour after treatment, J3.34 ± 1.1 at 2 hours after treatment, J3.93 ± 0.98 at 4 hours after treatment, and J4.98 ± 0.85 at 8 hours after treatment (p < 0.0001). At 12 hours post-treatment, the mean NVA was 6.75 ± 1.58J (p ═ 0.11). Mean Pupil Size (PS) was significantly reduced from 4.74 ± 0.47mm before treatment to 2.68 ± 0.41mm at 1 hour post-treatment, 3 ± 0.37mm at 2 hours post-treatment, 3.35 ± 0.4mm at 4 hours post-treatment, and 3.58 ± 0.43mm at 8 hours post-treatment (p < 0.0001). At 12 hours post-treatment, the mean pupil size was 4.51 ± 69mm (p ═ 0.12).

In group 2, mean Near Visual Acuity (NVA) improved significantly from J7.72 ± 1.48 before treatment to J1.36 ± 0.56 at 1 hour post-treatment, J1.4 ± 0.57 at 2 hours post-treatment, J1.8 ± 0.58 at 4 hours post-treatment, J2.32 ± 0.47 at 8 hours post-treatment, and 2.64 ± 0.7 at 12 hours post-treatment (p < 0.0001). Mean Pupil Size (PS) significantly decreased from 4.55 ± 0.55mm before treatment to 1.2 ± 0.25mm at 1 hour after treatment, 1.34 ± 0.31mm at 2 hours after treatment, 1.64 ± 0.3mm at 4 hours after treatment, 2 ± 0.28mm at 8 hours after treatment, and 2.27 ± 0.34mm at 12 hours after treatment (p < 0.0001).

In group 2, the improvement in near visual acuity was statistically significant up to 12 hours after treatment when 3% carbachol was instilled, while in group 1, the improvement in near visual acuity was significant up to 8 hours after treatment. Compared to the 2.25% concentration, 3% carbachol and brimonidine drops reported a significant improvement in mean NVA (p < 0.0001).

The mean change over time in Near Visual Acuity (NVA) (Jaeger) and Pupil Size (PS) (mm) for group 1 (2.25% carbachol plus brimonidine) versus group 2 (3% carbachol plus brimonidine) is shown in table 12 below.

Figures 23-23 show the mean change in near visual acuity (Jaeger) and pupil size (mm) over time for groups 1 and 2.

The composition of drops used in groups 1 and 2 also contained 100ppm benzalkonium chloride (BAK or BAC).

Burning, migraine, darkness or any other serious ocular adverse effects were not observed in any of the patients in both groups. No systemic side effects such as bradycardia, bronchospasm, and digestive problems were observed.

The uncorrected distance visual acuity for both eyes was 20/20 for all subjects prior to treatment and remained 20/20 for all time periods after treatment.

TABLE 12

Statistically significant improvements in mean near acuity (NVA) and mean Pupil Size (PS) were achieved in all subjects receiving both concentrations of carbachol plus brimonidine drops (p < 0.0001). Mean NVA and PS were reported to be significantly improved up to 12 hours post-treatment (p <0.0001) in all subjects receiving 3% carbachol drops. No serious ocular adverse effects were observed in the higher concentrations of carbachol.

Although the carbachol concentration varied between the two groups by 0.75%, an improvement in average NVA and PS was observed up to 12 hours post-treatment.

Based on this data, higher concentrations of carbachol were found to be safe and provide greater efficacy, with longer duration of action, in improving myopia acuity than lower concentrations.

Example 12

In one clinical study, 30 hyperopic subjects between the ages of 41 and 52 were divided into two groups. The mean age of each group was 47.5 ± 3.7 years (range, 41-52 years). Mean ages were not statistically significantly different. Group 1 received 3% bilateral dosing of 3% carbachol eye drops. Group 2 received bilateral administration of 3% carbachol plus 0.2% brimonidine eye drops. Drops were administered to both eyes of all subjects. Subjects were evaluated for pupil size and both near and far vision by blinded examiners under the same room lighting before and 1, 2, 4, 8, and 12 hours after treatment.

24 of 30 subjects (80%) gave up using spectacles for both distance and near vision, 4 subjects (13.4%) used spectacles for near vision only, with a diopter 2 to 3 lower than that required before treatment. Only two hyperopic subjects (6.6%) gave up treatment.

Example 13

One study investigated users of carbachol and brimonidine in combination with separate carbachol and brimonidine drops in correcting presbyopia (Clinical eyes of combined versules partial carbachol and brimonidine drops in corrected presbyopia, Abdelkader et al, Eye and Vision 2016; 3:31, which is incorporated herein by reference). The objective of this study was to improve near vision in presbyopic subjects by testing and comparing the efficacy of using parasympathomimetic drugs (3% carbachol) and alpha-2 agonists (0.2% brimonidine) in combination and separately to produce optically beneficial miosis in a blinded fashion to pharmacologically improve presbyopic vision.

Prospective double-blind randomized controlled clinical trials were performed. 10 natural emmetropic and presbyopic subjects aged between 42 and 58 years, with uncorrected hyperopic acuity for both eyes of at least 20/20 and without additional ophthalmologic disorders were eligible for inclusion. All subjects received 3% carbachol and 0.2% brimonidine, 3% carbachol alone and 0.2% brimonidine alone (control) in combined and separate forms in their non-dominant eye in a crossover fashion with a one week washout period between tests. Subjects were evaluated for pupil size and both near and far vision under the same room illumination by blinded examiners before and 1, 2, 4 and 8 hours after treatment.

All subjects receiving 3% carbachol and 0.2% brimonidine combined in the same formulation achieved a statistically significant improvement in mean Near Visual Acuity (NVA) (P <0.0001) compared to those receiving carbachol alone or brimonidine alone in separate forms. The combined solution showed higher efficacy than the other solutions tested. Improving the depth of focus by narrowing the pupil results in a statistically significant improvement in near visual acuity with no change in distance vision.

Participants were randomly selected volunteers. Presbyopia is considered to be present if the uncorrected end point print size ≧ Jaeger (J)5 improves ≧ 1 optotype with ≧ 1.00D of lens. All subjects were screened for good physical and ocular health and completed a questionnaire to determine any participating contraindications or predisposing complications (e.g. cardiac or respiratory disorders, migraine, high myopia, ocular or systemic medication or ocular surgery). All subjects performed a comprehensive mydriatic fundus examination before being considered eligible for the study. The screening is for drug contraindications, susceptibility to retinal detachment, ophthalmic disorders or peripheral retinal degeneration. Inclusion criteria were as follows: between the ages of 42 and 58, emmetropic [ mydriatic sphere power (SE), ± 0.25D; astigmatism, less than or equal to 0.25D and uncorrected hyperopic acuity of both eyes, greater than or equal to 20/20. Exclusion criteria included patients with myopia, hyperopia, and astigmatism above 0.25D diopters, as well as corneal, lens, and vitreous opacities, irregular pupils, unequal pupils, amblyopia, chronic common conditions, and patients whose medications would adversely interact with carbachol and brimonidine. All patients in this study did not receive any topical medications that could lead to mydriasis or miosis. During the study, subjects were closely monitored and periodically asked to report any ocular, systemic or physiological responses they experienced. Atropine can be used in the presence of adverse reactions, but no adverse reactions are reported. All procedures followed were in compliance with ethical standards of the human experimental responsibility committee.

A single dose of 3% carbachol with 0.2% brimonidine, as well as 3% carbachol alone or 0.2% brimonidine alone (control) in combination and divided form, was instilled in the non-dominant eye of the same 10 emmetropic presbyopic subjects with a one week washout period between tests. In the divided form, carbachol was first dropped and then brimonidine was dropped after 5 minutes. In a single dose of the combination of 3% carbachol and 0.2% brimonidine, 100ppm benzalkonium chloride was present. 3% carbachol drops contain 50ppm benzalkonium chloride. 0.2% brimonidine drops contain 50ppm benzalkonium chloride.

Initial pupil size and both near and far vision were recorded by the same independent examiner in the same room using the same instrument before and 1, 2, 4 and 8 hours after treatment. Distance vision was measured at 4m using a standard snellen projection chart. The handheld Rosenbaum visual acuity chart with Jaeger symbols is always adopted to be 160cd/m²At 40cm Near Visual Acuity (NVA) was assessed. Pupil Size (PS) was measured using a Colvard hand-held infrared pupillometer.

10 natural emmetropic and presbyopic subjects with a mean age of 49.7 ± 4.8 years (range, 42-58 years) were eligible for inclusion. These subjects (6 men and 4 women) had uncorrected hyperopic acuity for both eyes of at least 20/20 and no additional ophthalmological disorder.

In the combined drop group, mean Near Visual Acuity (NVA) improved significantly from J8.6 ± 1.5 before treatment to J1.1 ± 0.3 at 1 hour post-treatment, J1.1 ± 0.3 at 2 hours post-treatment, J1.8 ± 0.4 at 4 hours post-treatment, and J2.3 ± 0.5 at 8 hours post-treatment (P < 0.0001). Mean Pupil Size (PS) decreased significantly from 4.3 ± 0.5mm before treatment to 1.2 ± 0.3mm at 1 hour after treatment, 1.2 ± 0.3mm at 2 hours after treatment, 1.7 ± 0.2mm at 4 hours after treatment, and 2.1 ± 0.3mm at 8 hours after treatment (P < 0.0001).

In the divided drop group, mean NVA improved significantly from J8.6 ± 1.5 before treatment to J3.4 ± 1(P ═ 0.0002) at 1 hour after treatment, J3.6 ± 1(P ═ 0.0002) at 2 hours after treatment, J4.5 ± 1(P ═ 0.0004) at 4 hours after treatment, and J5.2 ± 0.8(P ═ 0.0008) at 8 hours after treatment. Mean (PS) decreased significantly from 4.3 ± 0.5mm before treatment to 1.9 ± 0.3mm at 1 hour after treatment, 2.2 ± 0.2mm at 2 hours after treatment, 2.5 ± 0.3mm at 4 hours after treatment, and 2.8 ± 0.2mm at 8 hours after treatment (P < 0.0001).

In the 3% carbachol group alone, mean NVA improved significantly from J8.6 ± 1.5 before treatment to J5.5 ± 1(P ═ 0.001) at 1 hour after treatment, J5.9 ± 0.8(P ═ 0.001) at 2 hours after treatment, J7 ± 1.2(P ═ 0.007) at 4 hours after treatment, and J7.5 ± 1(P ═ 0.027) at 8 hours after treatment. Mean (PS) decreased significantly from 4.3 ± 0.5mm before treatment to 2.8 ± 0.3mm (P ═ 0.0002) at 1 hour after treatment, 3 ± 0.3mm (P ═ 0.0002) at 2 hours after treatment, and 3.5 ± 0.3mm (P ═ 0.0007) at 4 hours after treatment. At 8 hours post-treatment, the mean (PS) was 4 ± 0.3mm (P ═ 0.15).

In the 0.2% brimonidine group alone, no statistically significant difference in mean NVA and mean (PS) was found at any time point before and after treatment (P > 0.05).

A significant improvement in mean NVA was reported in combined 3% carbachol and brimonidine drops (P <0.0001) compared to carbachol alone or separate carbachol or brimonidine alone.

Figures 27-28 show the mean change profile of near visual acuity and pupil size over time for this study.

Data from this study is shown in table 13 below.

Watch 13

None of the subjects complained of the pleriichz effect, which occurs due to intraocular differences in retinal illuminance caused by pupillary disparity. All subjects in our pilot study reported that they could be driven safely around the day and night without distorting any of the motor perceptions.

It was found that the near visual acuity was significantly improved (P <0.0001) in all subjects receiving the combined 3% carbachol and brimonidine in the same formulation compared to those receiving carbachol alone or brimonidine alone in separate forms.

This study attributed a significant improvement in the myopia acuity of subjects receiving the combination formulation to the penetration enhancers (benzalkonium chloride and carboxymethyl cellulose) added to the combination formulation, and possibly also to the fact that: when acting on both the receptor and the contractile muscle of the iris dilator, they reinforce each other more than when one is stimulated before the other, allowing maximum action with less cancellation.

Studies have shown that 0.2% brimonidine tartrate alone produces a slight miotic effect mainly within the first hour after instillation under brightness conditions, but this does not reach statistical significance (P > 0.05). In monocular therapy, the contralateral eye with a normal pupil has slightly blurred near vision, but distant objects are sharp and the perception of light is not diminished.

The study concluded that monocular drug treatment of presbyopia with one drop of carbachol and brimonidine per day in the non-dominant eye allowed many presbyopic subjects to have acceptable reading vision, even in elderly subjects.

In examples 11-13, carbachol alone, brimonidine alone, and carbachol plus brimonidine at various concentrations have been tested. Adding benzalkonium chloride preservative. To carbachol and brimonidine alone, 50ppm benzalkonium chloride was added. To carbachol plus brimonidine, 100ppm benzalkonium chloride was added.

The prior art has taught that benzalkonium chloride has known toxic effects and should be used with caution. The prior art also teaches away from the use of benzalkonium chloride concentrations in excess of 100ppm due to potential damage to corneal epithelial cells.

However, during the testing of 3% carbachol plus 0.2% brimonidine drops containing a combination of 100ppm benzalkonium chloride, separate administration of 3% carbachol containing 50ppm benzalkonium chloride followed by 0.2% brimonidine, administration of only 3% carbachol containing 50ppm benzalkonium chloride, and administration of only 0.2% brimonidine resulted in the average pupil size of presbyopic subjects reaching a target pupil size of ≦ 2.5mm within 1-8 hours in subjects administered 3% carbachol plus 0.2% brimonidine drops containing 100ppm benzalkonium chloride. As shown in figure 24, subjects administered only 3% carbachol containing 50ppm benzalkonium chloride never reached the target pupil size within 1-8 hours.

During the testing of 3% carbachol plus 0.2% brimonidine drops of a combination containing 100ppm benzalkonium chloride, separate administration of 3% carbachol containing 50ppm benzalkonium chloride followed by 0.2% brimonidine, administration of only 3% carbachol containing 50ppm benzalkonium chloride, and administration of only 0.2% brimonidine resulted in mean myopia acuity (NVA) of presbyopic subjects being greater than or equal to 20/40 within 1-8 hours in subjects being administered 3% carbachol plus 0.2% brimonidine drops containing 100ppm benzalkonium chloride. As shown in FIG. 25, subjects administered only 3% carbachol containing 50ppm benzalkonium chloride never reached an NVA of ≧ 20/40.

Figures 26a-26b show a very significant 12 hour effect on pupil size and NVA. The combination of 3% carbachol with 0.2% brimonidine and 100ppm benzalkonium chloride achieved a target pupil size of less than or equal to 2.5mm within 1-12 hours, exceeding 2.25% carbachol with 0.2% brimonidine and 100ppm combined drops. The combination of 3% carbachol with 0.2% brimonidine and 100ppm benzalkonium chloride achieved NVA of greater than or equal to 20/40 in 1-12 hours, exceeding 2.25% carbachol with 0.2% brimonidine and 100ppm combined drops.

Considering that brimonidine alone, containing 50ppm BAK, had little effect on NVA pupil size, the combination of carbachol, brimonidine and 100ppm BAK was not expected to exhibit a pharmacodynamic effect that was much greater in magnitude and duration. Furthermore, the pharmacodynamic effect is particularly unexpected when it is noted that drops of carbachol 3% and brimonidine 0.2% when administered as a combination reach a target pupil size of ≦ 2.5mm for 8 hours, while these same actives are administered separately with the same cumulative BAK exposure of about 100ppm at 5 minute intervals, reaching this target for only about 4 hours, and reaching the NVA target of 20/40 only at hour 1. Thus, applicants believe that the pharmacodynamic effect is not the result of the additive effect of any of the individual components, but is brought about by the new combination.

Example 14

One study investigated the effect of a combination treatment of carbachol and brimonidine tartrate on intraocular pressure in presbyopic adults. The combination of brimonidine and carbachol is expected to lower IOP by at least 4mm Hg, since brimonidine reduces aqueous products and uveoscleral outflow, while carbachol increases outflow through the trabecular meshwork. However, this did not happen, which was unexpected. Previous studies have only administered drugs to one eye, but examined both far and near visual acuity. Previous studies have relied on such preconditions: if the near vision of one eye is improved due to the pinhole effect, the near vision of both eyes will be the same or better than the treated eye. However, when parasympathomimetics are administered as the sole active ingredient, they cause ciliary body contraction and changes in lens shape, similar to when read at near distances. This lens change results in a significant myopia shift towards myopia in many patients and results in a blurred far vision.

Thus, the strategy of creating a pinhole effect using parasympathomimetics is to treat only one eye so that one eye maintains good distance vision. If a subject received a combination of brimonidine and carbachol in one eye and tested for distance vision in both eyes, the distance vision in both eyes remained 20/20 even though the subject lost distance vision due to myopia shifts in the dosed eye, since one eye remained untreated. The following study conducted a single eye test for intraocular pressure and distance vision in the same eyes receiving doses of brimonidine and carbachol. The evidence provided by this study indicates that distance vision is not affected by a formulation of 3% carbachol and 0.2% brimonidine tartrate, which is unexpected because carbachol alone causes loss of distance vision. This is novel if both eyes are treated while distance vision is preserved. It should also be noted that even though miotics alone can transiently increase and then decrease IOP in healthy subjects, there is no evidence of increased or decreased IOP in the combination of brimonidine and carbachol. This study is discussed below.

Prospective single-arm clinical trials were conducted. 16 subjects aged 42 to 58 (average 49.5) were enrolled, including 9 males and 7 females. 16 subjects were presbyopic, defined as uncorrected endpoint print size ≧ Jaeger (J)5, improvement ≧ 1 optotype in the case of use ≧ 1.00D lens; emmetropia, defined as the mydriatic sphere power ± 0.25D and astigmatism no more than 0.25D; uncorrected distance vision in both eyes is at least 20/20; no additional ophthalmic disorder; and the overall health is good. All subjects received 3% carbachol and 0.2% brimonidine tartrate. Study drug topical application to non-dominant eye; the dominant eye was untreated and served as a control.

Intraocular pressure (IOP) was measured using a hand-held tonometer (Tono-Pen). The 4 measurements were averaged and those measurements with poor signal or extreme readings were discarded. At baseline, all subjects were normotensive, with an average IOP of 13.8mm HG for the treated eye and 14.5mm HG for the control eye. No significant change in IOP was observed in any of the eyes. The results of this single dose study showed no significant effect on IOP when 3% carbachol and 0.2% brimonidine tartrate were administered in combination to normotensive presbyopic subjects. This is a particularly important finding for the treatment of patients with elevated intraocular pressure in glaucoma, who are widely available for undiagnosed, where IOP fluctuations are undesirable. The results of the study are shown in table 14.

Accordingly, it is to be understood that the embodiments of the invention herein described are merely illustrative of the application of the principles of the invention. Reference herein to details of the illustrated embodiments is not intended to limit the scope of the claims which themselves recite those features regarded as essential to the invention.

Claims (72)

1. A method for improving or reducing at least one refractive error in a pseudolens patient, the refractive error selected from myopia, hyperopia and astigmatism, the method comprising:

administering to at least one eye of the patient an ophthalmic formulation comprising:

a therapeutically effective amount of one or more parasympathomimetic agents or pharmaceutically acceptable salts thereof; and

a therapeutically effective amount of an alpha agonist or an alpha antagonist or a pharmaceutically acceptable salt thereof.

2. The method of claim 1, wherein the alpha agonist is brimonidine.

3. The method of claim 2, wherein brimonidine is present in the formulation in an amount of about 0.05-0.3%.

4. The method of claim 1, wherein the parasympathomimetic agent is carbachol.

5. The method of claim 4, wherein carbachol is present in the formulation in an amount of about 0.5-5%.

6. The method of claim 1, wherein the parasympathomimetic agent is carbachol and the alpha agonist is brimonidine.

7. The method of claim 1, wherein the parasympathomimetic agent is pilocarpine.

8. The method of claim 7, wherein pilocarpine is present in an amount from about 0.25% to about 1.5%.

9. The method of claim 1 wherein the alpha agonist is phentolamine.

10. The method of claim 9 wherein phentolamine is present in an amount of less than about 2%.

11. The method of claim 1, wherein the formulation is administered to one eye.

12. The method of claim 1, wherein the formulation is administered to both eyes.

13. The method of claim 1, wherein the parasympathomimetic agent and the alpha agonist are combined in a single formulation.

14. The method of claim 1, wherein the ophthalmic formulation further comprises tropicamide.

15. A method of treating at least one refractive error in a patient having undergone eye surgery, comprising:

administering to at least one eye of said patient an ophthalmic formulation comprising:

a therapeutically effective amount of one or more parasympathomimetic agents or pharmaceutically acceptable salts thereof; and

a therapeutically effective amount of an alpha agonist or an alpha antagonist or a pharmaceutically acceptable salt thereof.

16. The method of claim 15, wherein the alpha agonist is brimonidine.

17. The method of claim 16, wherein brimonidine is present in the formulation in an amount of about 0.05-0.3%.

18. The method of claim 15, wherein the parasympathomimetic agent is carbachol.

19. The method of claim 18, wherein carbachol is present in the formulation in an amount of about 0.5-5%.

20. The method of claim 15, wherein the parasympathomimetic agent is carbachol and the alpha agonist is brimonidine.

21. The method of claim 15, wherein the parasympathomimetic agent is pilocarpine.

22. The method of claim 21, wherein pilocarpine is present in an amount from about 0.25% to about 1.5%.

23. The method of claim 15, wherein the alpha agonist is phentolamine.

24. The method of claim 23 wherein phentolamine is present in an amount of less than about 2%.

25. The method of claim 15, wherein the formulation is administered to one eye.

26. The method of claim 15, wherein the formulation is administered to both eyes.

27. The method of claim 15 wherein the parasympathomimetic agent and the alpha agonist are combined in a single formulation.

28. The method of claim 15, wherein the ophthalmic formulation further comprises tropicamide.

29. The method of claim 15, wherein the refractive error is selected from the group consisting of myopia, hyperopia, astigmatism, and any combination of myopia, hyperopia, and astigmatism.

30. The method of claim 15, wherein the surgery is laser surgery.

31. The method of claim 15, wherein the procedure comprises replacing at least one natural lens with an artificial intraocular lens.

32. The method of claim 31, wherein the ophthalmic formulation temporarily restores multifocal to at least one of the eyes having the intraocular lens.

33. A method of producing multifocal, presbyopic symptoms in a pseudolens patient in a patient having one eye or both eyes comprising: administering to one or both eyes with presbyopia a pharmaceutically effective amount of an ophthalmic formulation comprising at least a therapeutically effective amount of one or more parasympathomimetic agents or pharmaceutically acceptable salts thereof; and a therapeutically effective amount of an alpha agonist or an alpha antagonist or a pharmaceutically acceptable salt thereof.

34. The method of claim 33, wherein the alpha agonist is brimonidine.

35. The method of claim 34, wherein brimonidine is present in the formulation in an amount of about 0.05-0.3%.

36. The method of claim 33, wherein the parasympathomimetic agent is carbachol.

37. The method of claim 35, wherein carbachol is present in the formulation in an amount of about 0.5-5%.

38. The method of claim 33, wherein carbachol is present in the formulation in an amount of about 2.25-3.5%.

39. The method of claim 33, wherein the parasympathomimetic agent is carbachol and the alpha agonist is brimonidine.

40. The method of claim 33 wherein the alpha agonist is phentolamine.

41. The method of claim 78 wherein phentolamine is present in an amount of less than about 2%.

42. The method of claim 33, wherein the formulation is administered to one eye.

43. The method of claim 33, wherein the formulation is administered to both eyes.

44. The method of claim 33 wherein the parasympathomimetic agent and the alpha agonist are combined in a single formulation.

45. The method of claim 33, wherein the ophthalmic formulation further comprises tropicamide.

46. The method of claim 33, wherein the patient's eye or eyes comprise an artificial intraocular lens.

47. The method of claim 45, wherein said ophthalmic formulation temporarily restores multifocal to at least one of said eyes having said intraocular lens.

48. The method of claim 1, wherein the ophthalmic formulation further comprises benzalkonium chloride present in an amount of about 0.005-0.1%.

49. The method of claim 15, wherein the ophthalmic formulation further comprises benzalkonium chloride present in an amount greater than 0.005%.

50. A method of producing multifocal, presbyopic symptoms in a pseudolens patient in a patient having one eye or both eyes comprising: administering to one or both eyes with presbyopia a pharmaceutically effective amount of an ophthalmic formulation comprising at least a therapeutically effective amount of one or more parasympathomimetic agents or pharmaceutically acceptable salts thereof; a therapeutically effective amount of an alpha agonist or an alpha antagonist or a pharmaceutically acceptable salt thereof; and a penetration enhancer.

51. The method of claim 50, wherein the alpha agonist is brimonidine.

52. The method of claim 50, wherein the parasympathomimetic agent is carbachol.

53. The method of claim 50, wherein the benzalkonium chloride is present in an ophthalmic formulation in an amount of about 0.005-0.1%.

54. A method for improving or reducing at least one refractive error in a pseudolens patient, the refractive error selected from myopia, hyperopia and astigmatism, the method comprising:

administering to at least one eye of a patient an ophthalmic formulation comprising:

a therapeutically effective amount of one or more parasympathomimetic agents or pharmaceutically acceptable salts thereof; and

a penetration enhancer.

55. The method of claim 54, wherein the parasympathomimetic agent is carbachol.

56. The method of claim 54, wherein the penetration enhancer is benzalkonium chloride and is present in the ophthalmic formulation in an amount of about 0.005-0.1%.

57. The method of claim 15, further comprising a penetration enhancer for benzalkonium chloride.

58. The method of claim 57, wherein the parasympathomimetic agent is carbachol.

59. The method of claim 57, wherein benzalkonium chloride is present in the ophthalmic formulation in an amount of about 0.005-0.1%.

60. A method of producing multifocal, presbyopia symptom relief in a pseudocrystalline patient having one eye or both eyes, comprising: administering to one or both eyes with presbyopia a pharmaceutically effective amount of an ophthalmic formulation comprising at least a therapeutically effective amount of one or more parasympathomimetic agents or pharmaceutically acceptable salts thereof; and a penetration enhancer.

61. The method of claim 60, wherein the parasympathomimetic agent is carbachol.

62. The method of claim 60, wherein the benzalkonium chloride is present in an ophthalmic formulation in an amount of about 0.005-0.1%.

63. A method for improving or reducing at least one refractive error in a pseudolens patient, the refractive error selected from myopia, hyperopia and astigmatism, the method comprising:

administering to one or both eyes of a patient an ophthalmic formulation comprising:

a therapeutically effective amount of one or more parasympathomimetic agents or pharmaceutically acceptable salts thereof; and

a therapeutically effective amount of an alpha agonist or alpha antagonist or a pharmaceutically acceptable salt thereof;

wherein at least intermediate vision of a pseudophakic patient is improved by administering the ophthalmic formulation to one or both eyes of the patient.

64. The method of claim 63, wherein the ophthalmic formulation further comprises a penetration enhancer.

65. The method of claim 63, wherein the alpha agonist is brimonidine.

66. The method of claim 63, wherein the parasympathomimetic agent is carbachol.

67. The method of claim 64, wherein the penetration enhancer is benzalkonium chloride and is present in the ophthalmic formulation in an amount of about 0.005-0.1%.

68. The method of claim 63, wherein the parasympathomimetic is pilocarpine.

69. The method of claim 63, wherein the parasympathomimetic agent is carbachol and the alpha agonist is brimonidine.

70. A method of preventing parasympathomimetic-induced myopia metastasis in a pseudomorphic patient receiving a parasympathomimetic, or a pharmaceutically acceptable salt thereof, comprising:

administering to both eyes of the pseudolens patient an ophthalmic formulation comprising:

a therapeutically effective amount of one or more parasympathomimetic agents or pharmaceutically acceptable salts thereof; and

a therapeutically effective amount of an alpha 2 agonist or a pharmaceutically acceptable salt thereof,

wherein the ophthalmic formulation increases depth of focus and maintains distance visual acuity while preventing parasympathomimetic-induced myopia progression in both dosed eyes of the pseudolens patient.

71. The method of claim 70, wherein the parasympathomimetic agent is carbachol.

72. The method of claim 70, wherein the parasympathomimetic agent is carbachol and the alpha 2 agonist is brimonidine.

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